presentation about zinc

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What Is Zinc?

• Side Effects

Precautions

Interactions.

• How to Store

Similar Supplements

• Sources & What to Look For

People only need a small amount of zinc, but it plays an important role in the body. Zinc is integral in DNA creation, immune support , cell growth, tissue healing, protein building, and the senses. It is necessary for healthy growth during childhood, adolescence, and pregnancy.

A zinc deficiency can cause problems with wound healing, slow growth, loss of taste and smell, and cognitive problems. If severe, it can even cause death. In most industrialized countries, zinc deficiencies are fairly rare, although they can occur in certain populations.

Read on to find out more information about why someone might need zinc supplementation, foods to eat to get enough zinc, and how to safely supplement with it.

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Dietary supplements are not regulated the way drugs are in the United States, which means the Food and Drug Administration (FDA) does not approve them for safety and effectiveness before the products are marketed. When possible, choose a supplement tested by a trusted third party, like USP, ConsumerLabs, or NSF.

Remember that third-party testing does not guarantee safety or effectiveness. It’s important, then, to talk with your healthcare provider about any supplements you plan to take, and ask about any potential interactions with other supplements or medications.

Supplement Facts

• Active ingredient : Zinc
• Alternate names : Zinc sulfate, zinc picolinate, zinc glycerate, zinc citrate, zinc acetate, zinc monomethionine
• Legal status : Over the counter
• Suggested dose : Supplements are generally 30 to 50 milligrams (mg) each. Follow instructions on the label or per your healthcare provider's instructions.
• Safety considerations : Before taking supplements, check with your healthcare provider to see if there are potential interactions with any other supplements or medications you are taking and if it is safe and appropriate for you to take zinc.

Benefits of Zinc

Supplement use is unique to each person and should be vetted by a healthcare professional, such as a registered dietitian, pharmacist, or healthcare provider. No supplement is intended to treat, cure, or prevent disease. Ask your healthcare provider before starting to use any supplement whether it is safe and appropriate for you.

Most people get enough zinc by eating a healthy and varied diet and by taking a multivitamin. The recommended daily allowance for adults is between 8 mg and 11 mg, and it can vary if you are pregnant or lactating.

For people in industrialized countries, the likelihood of being significantly deficient in zinc is rare. People who may have lowered zinc levels include older people and those with alcohol use disorder, anorexia, or who are on severely restricted diets.

Those with conditions with malabsorption problems, like Crohn’s disease or celiac disease , as well as those who’ve had bariatric (weight-loss) surgery , may also have zinc deficiencies.

Zinc supplementation may be suggested to help with:

• Acne : People with acne often have lowered serum zinc levels, and both oral and topical zinc have been found to reduce the prevalence of inflammatory papules, both when used as monotherapy and as a supplemental therapy.
• Age-related macular degeneration (AMD) : AMD is an eye condition affecting a part of the light-sensitive retina. Zinc is included in the Age-Related Eye Disease Studies (AREDS and AREDS2) formulas that contain other vitamins and minerals. These supplements have been found beneficial for people with intermediate or late AMD in clinical trials, but they don't prevent AMD or help in early AMD.
• Attention deficit hyperactivity disorder (ADHD) : Studies of zinc levels in people with ADHD have been inconsistent. A meta-analysis found that those living with ADHD might be more likely to have lower zinc levels, and therefore screening for zinc deficiency—and then supplementing—might be useful.
• Bone health : Zinc plays a key role in bone development and bone repair. Researchers suspect zinc may also work to prevent osteoporosis. However, the optimal dose is unclear, and more studies are needed.  
• Colds (as lozenges): Zinc lozenges may help prevent cold symptoms or shorten the length of a cold, but the studies have had a high risk of bias (being sponsored by drug companies), had small numbers of participants, or used different methods and are hard to compare.
• Preventing chronic conditions : Zinc is an antioxidant that helps combat oxidative stress. Studies show zinc lowers markers of systemic inflammation. Inflammation and oxidative stress are associated with several chronic conditions, including arthritis, heart disease, kidney disease, and neurological conditions like Alzheimer’s, Parkinson’s, and multiple sclerosis.  Scientists suspect zinc supplements may help to prevent chronic diseases, though more research is needed.
• Sickle cell disease : Sickle cell disease is an inherited condition affecting the red blood cells. Many people with sickle cell disease are deficient in zinc, which can cause lowered immunity and increased risk of infection. Supplementing with zinc can lower both disease-associated morbidity as well as infections.
• Type 2 diabetes : Zinc may help lower blood sugar and cholesterol in people with type 2 diabetes. Research ties zinc supplements to reduced levels of fasting glucose, post-meal blood sugar, triglyceride, total cholesterol, and LDL cholesterol. Zinc deficiency may also play a role in the development of type 2 diabetes.

If you have any of these conditions, talk with your healthcare provider. You may have to take high doses of the supplement for a small period of time, under the supervision of a professional. Many studies of zinc treatments for different conditions have proven not to be clinically significant, or the dosage of zinc would be so high that it’s dangerous.

What Are the Side Effects of Zinc?

Zinc supplements can cause various side effects. They may be common or severe, depending on how much zinc you take and other factors.

Common Side Effects

Most people taking zinc supplements have little to no side effects, although like any vitamin/mineral supplement, zinc can cause slight upset stomach if taken without food. Take zinc with water or juice, and not at the same time as any iron or calcium supplements.

A good time to take the supplement is right after breakfast, depending on when you take other supplements.

Severe Side Effects

Severe side effects can happen if you take too much zinc, and can include:

• Nausea and vomiting
• Loss of appetite
• Stomach pain or cramping

Zinc nasal sprays or nasal gels have been associated with a loss of sense of smell for some people.

You don’t need a lot of zinc to be healthy. Zinc is what is known as a trace mineral. Most people get what they need from dietary sources. Because of the potential for significant adverse effects and interactions with medications or other supplements, it should be used under the supervision of your healthcare provider.

Dosage: How Much Zinc Should I Take?

People of different ages need different amounts of zinc, and most people get enough from their diet and multivitamins. People who are pregnant and/or breastfeeding need more zinc because of their bodily demands and needs.

For children ages birth to 13, recommended dietary allowances (RDAs) range from 2 mg to 8 mg, depending on age. Teenagers age 14 to 18 need 11 mg for males, 9 mg for females, 12 mg if pregnant, and 13 mg if breastfeeding.

Adult males 19 and older should get 11 mg daily; adult females 19 and older, 8 mg;people who are pregnant or breastfeeding, 11 mg and 12 mg, respectively.

(Note that Verywell Health prefers to use inclusive terminology. But when citing health authorities or research, the terms for sex or gender from those sources are used.)

A regular multivitamin is generally enough for most adults, but children, pregnant and nursing people, and older adults should see a healthcare provider to assess what kind of supplementation they need.

Eating a healthy and varied diet and taking a daily multivitamin usually provides all the zinc you need, without extra zinc supplementation. If supplementation is needed, it is typically done over limited periods of time, taking plenty of breaks. Your healthcare provider can talk with you more about whether extra zinc supplementation is necessary and the length of time you should be on it.

If you are a vegetarian or vegan, talk with your healthcare provider about your diet to see whether you are getting all the nutrients you need, including zinc. A prenatal vitamin may be enough for pregnant and nursing people.

But if a child or older adult is deficient, they may need specific doses of zinc supplementation under the supervision of a healthcare provider. Do not give zinc supplements to a child without the instructions of a healthcare provider.

What Happens if I Take Too Much Zinc?

There have been no reports of getting too much zinc through diet, but there is a danger of zinc toxicity from supplements. To avoid toxicity, be aware of the proper dosage, and be mindful of the suggested upper limit of the supplement.

For adults, the upper tolerable limit of daily intake of zinc, which includes from both food and supplements, is 40 mg. Too much zinc can cause side effects such as:

• Nausea and/or vomiting

It’s not good to take zinc supplements for long periods of time, especially every day. If you take too much zinc for prolonged periods of time, you can lower your own natural immunity, impair your body’s ability to absorb magnesium, and lower your high-density lipoprotein (HDL) cholesterol, considered the “good” cholesterol.

Chronic and excessive zinc supplementation can cause copper deficiency and neurological problems as well.

An ongoing prospective cohort study (one that follows participants over many years) of U.S. males found those who took high levels of supplemental zinc (more than 75 milligrams per day) were at higher risk for prostate cancer, and those who took supplemental zinc for more than 15 years were also at higher risk for lethal and more aggressive prostate cancer.

If you think you’ve taken too much zinc, contact the poison control hotline or go to the emergency room.

Even though they're not prescriptions, supplements can interact with food, medications, or other supplements. Sometimes this can be dangerous and cause serious adverse effects. With zinc, interactions can include:

• Various antibiotics can lower zinc levels and interfere with your body’s absorption of zinc; take the antibiotic two hours before the supplement, or four to six hours after the supplement.
• The drug Cuprimine (penicillamine) for rheumatoid arthritis and Wilson's disease ( a condition in which there are high amounts of copper in the body) can be modified by zinc supplements, so take the zinc and the medication at least one hour apart.
• Certain diuretics (water pills) increase the volume of zinc lost in the urine, lowering zinc levels in the body.

This is not a complete list of interactions; before taking zinc supplements, ask a healthcare provider if it is safe for you to take them.

It’s very important to read the ingredient list and nutrition facts panel of a supplement so you know what is in it. Please review this information with a healthcare provider to discuss any possible interactions with foods or any other medications or supplements that you take.

How to Store Zinc

As with many vitamin and mineral supplements, light, heat, and humidity can all impact the quality and integrity of zinc supplements. Store your supplements in a cool, dark, and dry place. Do not store in the refrigerator or leave it in the bathroom, where there is too much moisture.

Keep zinc supplements away from direct sunlight. Discard the supplements as indicated on the packaging.

Zinc is often used to supplement or boost the immune system or improve skin conditions, but other supplements do that, as well. Similar supplements can include, but are not limited to:

• Vitamin A (retinol)
• Vitamin C (ascorbic acid)
• Omega-3 fatty acids
• Coenzyme Q10 (CoQ10)
• Alpha-linolenic acid (ALA)
• Vitamin B3 (niacin)

If you are taking more than one supplement, ask your healthcare provider if they should be taken alongside each other.

Sources of Zinc and What to Look For

The best way to get enough zinc is through your diet. If this isn’t possible, fortified foods and supplements can be added. For vegetarians and vegans, legumes (peas, beans, lentils) and whole grains can inhibit the absorption of zinc, so supplementation might be necessary.

Food Sources of Zinc

Foods that contain zinc include:

• Some seafood, like crab and lobster
• Fortified cereals

Foods that have some zinc, but not as much, include beans, nuts, whole grains, eggs, and dairy products.

Zinc Supplements

Nearly all of the general multivitamin and mineral dietary supplements have zinc in them. You can also get an isolated zinc supplement or a supplement in which zinc is combined with something like calcium.

There are different forms of zinc in supplements, but one has not been shown to be better than the others. Sometimes zinc is also in denture adhesives or homeopathic remedies.

Zinc is an important mineral for good health, growth, immune support, and overall functioning. While most people get all the zinc they need from a healthy and varied diet and a multivitamin, some people may need to supplement a bit more.

Because the body only needs a small amount of zinc, it can be easy to take too much and experience negative side effects. Talk with a healthcare provider about whether supplementation is necessary, and the possibility of any adverse interactions with your existing medication and supplement consumption.

National Institutes of Health Office of Dietary Supplements. Zinc fact sheet for professionals .

Mount Sinai. Zinc .

Yee BE, Richards P, Sui JY, Marsch AF. Serum zinc levels and efficacy of zinc treatment in acne vulgaris: A systematic review and meta-analysis . Dermatologic Therapy . 2020;33(6). doi:10.1111/dth.14252

National Eye Institute. AREDS/AREDS2 frequently asked questions .

Ghoreishy SM, Mousavi SE, Asoudeh F, Mohammadi H. Zinc status in attention deficit/hyperactivity disorder: a systematic review and meta-analysis of observational studies . Sci Rep . 2021;11. doi:10.1038/s41598-021-94124-5

O'Connor JP, Kanjilal D, Teitelbaum M, Lin SS, Cottrell JA. Zinc as a therapeutic agent in bone regeneration . Materials (Basel). 2020;13(10):2211. doi:10.3390/ma13102211

Hunter J, Arentz S, Goldenberg J, et al. Zinc for the prevention or treatment of acute viral respiratory tract infections in adults: a rapid systematic review and meta-analysis of randomised controlled trials . BMJ Open . 2021;11(11):e047474. doi:10.1136/bmjopen-2020-047474

Mousavi SM, Hajishafiee M, Clark CCT, et al. Clinical effectiveness of zinc supplementation on the biomarkers of oxidative stress: A systematic review and meta-analysis of randomized controlled trials . Pharmacol Res . 2020;161:105166. doi:10.1016/j.phrs.2020.105166

Pizzino G, Irrera N, Cucinotta M, et al. Oxidative stress: harms and benefits for human health . Oxid Med Cell Longev . 2017;2017:8416763. doi:10.1155/2017/8416763  

Olechnowicz J, Tinkov A, Skalny A, Suliburska J. Zinc status is associated with inflammation, oxidative stress, lipid, and glucose metabolism . J Physiol Sci . 2018;68(1):19-31. doi:10.1007/s12576-017-0571-7

Miranda CTOF, Vermeulen-Serpa KM, Pedro ACC, Brandao-Neto J, Vale SHL, Figueiredo MS. Zinc in sickle cell disease: a narrative review . Journal of Trace Elements in Medicine and Biology . 2022;72. doi:10.1016/j.jtemb.2022.126980

Wang X, Wu W, Zheng W, et al. Zinc supplementation improves glycemic control for diabetes prevention and management: a systematic review and meta-analysis of randomized controlled trials . Am J Clin Nutr . 2019;110(1):76-90. doi:10.1093/ajcn/nqz041

Harvard T. H. Chan School of Public Health. Zinc .

National Institutes of Health Office of Dietary Supplements. Zinc fact sheet for consumers .

Zhang Y, Song M, Mucci LA, Giovanucci EL. Zinc supplement use and risk of aggressive prostate cancer: A 30-year follow-up study . European Journal of Epidemiology . 2022 Nov 3:1–10. doi:10.1007/s10654-022-00922-0

DailyMed. PR NATAL 400- beta carotene, ascorbic acid, cholecalciferol, .alpha.-tocopherol acetate, dl-, thiamine mononitrate, riboflavin, niacinamide, pyridoxine hydrochloride, folic acid, cyanocobalamin, calcium carbonate, iron protein succinylate, ferrous bisglycinate, magnesium oxide, zinc oxide, cupric oxide tablet kit .

By Jaime R. Herndon, MS, MPH Herndon is a freelance health/medical writer with a graduate certificate in science writing from Johns Hopkins University.

Zinc is a trace mineral, meaning that the body only needs small amounts, and yet it is necessary for almost 100 enzymes to carry out vital chemical reactions. It is a major player in the creation of DNA, growth of cells, building proteins, healing damaged tissue, and supporting a healthy immune system . [1] Because it helps cells to grow and multiply, adequate zinc is required during times of rapid growth, such as childhood, adolescence, and pregnancy. Zinc is also involved with the senses of taste and smell.

Recommended Amounts  

RDA:  The Recommended Dietary Allowance (RDA) for adults 19+ years is 11 mg a day for men and 8 mg for women. Pregnancy and lactation requires slightly more at 11 mg and 12 mg, respectively.

UL:   The Tolerable Upper Intake Level is the maximum daily intake unlikely to cause harmful effects on health. The UL for zinc is 40 mg daily for all males and females ages 19+ years.

Zinc and Health

Because zinc supports the growth and normal functioning of immune cells, even a mild or moderate deficiency can slow down the activity of lymphocytes, neutrophils, and macrophages that protect the body from viruses and bacteria. Zinc deficiency is a common health problem in children from low and middle-income countries that contributes to stunting of growth, diarrhea, pneumonia, and malaria. [2] The elderly who may have low zinc intakes from a poor appetite due to multiple diseases and medications are at risk for infections, such as pneumonia and skin ulcers, as reviewed in the next section.

Adequate zinc is needed to create new cells, particularly collagen and fiber-like tissues, a necessary function in repairing damaged cells. Zinc also supports immune cell activity that combats inflammation from a wound. Therefore the greatest benefit of zinc appears to be in people who are deficient in the mineral and who have severe wounds such as decubitus ulcers or extensive burns. Because people with these conditions have higher zinc needs and may have poor appetites, supplements or topical creams are used rather than relying on food intake alone. In these cases, zinc is often combined with other nutrients like protein, vitamin C, and L-arginine that also promote wound healing such as in a nutritional shake. [3] However, a benefit of zinc supplementation has not been shown in people with skin ulcers who have normal blood levels of zinc. [4]

Food Sources

Meats, poultry, and seafood are rich in zinc. Some plant foods like legumes and whole grains are also good sources of zinc, but they also contain phytates that can bind to the mineral, lowering its absorption.

• Shellfish: oysters, crab, lobster
• Nuts , seeds
• Whole grains
• Fortified breakfast cereals

Supplements

Zinc is available in supplement form as pills and lozenges. Excess zinc can interfere with the absorption of iron and copper. High doses can also cause nausea and even vomiting. Therefore it is important not to take supplemental zinc unless it is known that the diet is low in foods containing zinc or a zinc deficiency is confirmed. A registered dietitian can help to evaluate one’s diet and determine if zinc intake is low.

What about the use of zinc lozenges for colds?

Zinc is believed to prevent cold viruses from spreading and by reducing inflammation, which may shorten the duration of a cold. Research has shown mixed results of their effectiveness due to differences in the form of zinc, the dosage, and how long it was used. Yet some clinical trials support its effectiveness. A Cochrane review of clinical trials found that zinc lozenges did not prevent colds, but if taken within a day of the onset of cold symptoms (sore throat, sniffles), the lozenges could tame its severity. [5] However, it is noted that some of the trials were funded by pharmaceutical companies who may have had financial interest in or produced zinc lozenges.

Zinc lozenges can carry a few unpleasant side effects like having a metallic flavor and causing nausea, but some people would gladly trade these symptoms for a bout with a nasty cold.

Signs of Deficiency and Toxicity

A zinc deficiency is rare and is seen most commonly in people who do not absorb zinc well due to digestive disorders such as inflammatory bowel diseases or who have undergone gastrointestinal surgery. Those with chronic liver or kidney disease are also at risk. Excessive or prolonged diarrhea can lead to a zinc deficiency, as well as severe conditions with increased zinc needs like burns and sepsis (an infection caused by harmful bacteria entering the blood). Zinc is more efficiently absorbed when taken in smaller doses and in people who are deficient in the mineral.

Other groups at risk for zinc deficiency:

• Pregnant women. Increased zinc needs for the fetus and during lactation.
• Low amounts of zinc in human breast milk. High amounts of calcium and phosphorus in cow’s milk can lower zinc absorption.
• Vegetarians/vegans. Zinc intake is limited to plant foods like whole grains that have lower bioavailability than from animal foods.
• Decreased absorption and increased loss of zinc through the urine.

Signs of deficiency include:

• Loss of taste or smell
• Poor appetite
• Depressed mood
• Decreased immunity
• Delayed wound healing

Toxicity occurs almost exclusively from zinc supplements rather than food. There have been no reports of eating too much zinc from the diet alone. [1]

Signs of toxicity include:

• Nausea, vomiting
• Abdominal pain or cramping

Did You Know?

Zinc oxide was used in ointments to treat wounds, as noted in ancient Greek medical texts. Today, zinc oxide is still a popular over-the-counter treatment skin treatment. It can defend against sunburns by reflecting and scattering ultraviolet rays so they do not penetrate the skin. It is also used to treat inflamed skin conditions like burns, eczema, bedsores, and diaper rash. The compound forms a protective barrier on the skin’s surface, repelling away moisture and allowing the skin to heal. It may also aid enzymes to break down damaged collagen tissue so that new tissue can be formed. No negative side effects have been reported.

Vitamins and Minerals

• Institute of Medicine. Food and Nutrition Board. Dietary Reference Intakes for Vitamin A, Vitamin K, Arsenic, Boron, Chromium, Copper, Iodine, Iron, Manganese, Molybdenum, Nickel, Silicon, Vanadium, and Zinc: a Report of the Panel on Micronutrients. Washington, DC: National Academy Press; 2001. https://www.ncbi.nlm.nih.gov/books/NBK222317/ Accessed 10/17/2019.
• Mayo‐Wilson E, Junior JA, Imdad A, Dean S, Chan XH, Chan ES, Jaswal A, Bhutta ZA. Zinc supplementation for preventing mortality, morbidity, and growth failure in children aged 6 months to 12 years of age. Cochrane Database of Systematic Reviews . 2014(5).
• Ellinger S, Stehle P. Efficacy of vitamin supplementation in situations with wound healing disorders: results from clinical intervention studies. Current Opinion in Clinical Nutrition & Metabolic Care . 2009 Nov 1;12(6):588-95.
• Wilkinson EA. Oral zinc for arterial and venous leg ulcers. Cochrane Database of Systematic Reviews . 2014(9).
• Singh M, Das RR. Zinc for the common cold. Cochrane Database Syst Rev . 2011 Feb 16;(2):CD001364.

Last reviewed March 2023

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Topic summary contributed by volunteer(s): Mimi

Zinc is an essential trace mineral that plays an important role in the body and is best known for its immunity-boosting and wound-healing qualities. A variety of foods contain zinc, with high levels found in beef , shellfish, spinach , beans , legumes , nuts , seeds , and whole grains .

Phytates and Zinc Absorption

Phytate is a naturally occurring compound found in all plant foods like beans, grains, nuts, and seeds. In the past, there were concerns that foods high in phytates might reduce absorption of minerals like zinc. However, recent studies show that this so-called “anti-nutrient” effect occurs when large amounts of phytates are consumed with a diet that is poor in nutrition.

Zinc from plant foods is not absorbed as well as zinc from animal foods, which may be a concern for vegetarians . In fact, a 2009 study revealed that vegetarians may be at risk for zinc deficiency. Vegetarians in the study had low blood zinc levels due to the high intake of phytates in their diet.

Zinc Gel for Colds: Helpful or Harmful?

Zinc gels, marketed to shorten colds and give relief from allergies and nasal congestion, have proven to be harmful.  In 2009, after 130 reports of loss of smell associated with the use of zinc gel, the U.S. Food and Drug Administration advised consumers to stop using these over-the-counter products as cold remedies. The loss of smell may be long-term or permanent.

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Role of zinc in health and disease

Lucy i. stiles.

1 Faculty of Life Sciences and Medicine, GKT School of Medical Education, King’s College London, London, UK

Kevin Ferrao

Kosha j. mehta.

2 Faculty of Life Sciences and Medicine, Centre for Education, King’s College London, London, UK

This review provides a concise overview of the cellular and clinical aspects of the role of zinc, an essential micronutrient, in human physiology and discusses zinc-related pathological states. Zinc cannot be stored in significant amounts, so regular dietary intake is essential. ZIP4 and/or ZnT5B transport dietary zinc ions from the duodenum into the enterocyte, ZnT1 transports zinc ions from the enterocyte into the circulation, and ZnT5B (bidirectional zinc transporter) facilitates endogenous zinc secretion into the intestinal lumen. Putative promoters of zinc absorption that increase its bioavailability include amino acids released from protein digestion and citrate, whereas dietary phytates, casein and calcium can reduce zinc bioavailability. In circulation, 70% of zinc is bound to albumin, and the majority in the body is found in skeletal muscle and bone. Zinc excretion is via faeces (predominantly), urine, sweat, menstrual flow and semen. Excessive zinc intake can inhibit the absorption of copper and iron, leading to copper deficiency and anaemia, respectively. Zinc toxicity can adversely affect the lipid profile and immune system, and its treatment depends on the mode of zinc acquisition. Acquired zinc deficiency usually presents later in life alongside risk factors like malabsorption syndromes, but medications like diuretics and angiotensin-receptor blockers can also cause zinc deficiency. Inherited zinc deficiency condition acrodermatitis enteropathica, which occurs due to mutation in the SLC39A4 gene (encoding ZIP4), presents from birth. Treatment involves zinc supplementation via zinc gluconate, zinc sulphate or zinc chloride. Notably, oral zinc supplementation may decrease the absorption of drugs like ciprofloxacin, doxycycline and risedronate.

Introduction

Significance of zinc in human health.

Zinc cannot be synthesised within the human body, so external intake of zinc is essential to maintain adequate levels in the body [ 1 ]. It is the second most abundant trace element in the body, after iron [ 2 ]. One in ten proteins found in the body is a zinc protein [ 3 ], and more than 300 enzymes and 1000 transcription factors depend on zinc for their activities [ 4 ]. Thus, zinc is an essential micronutrient involved in many cellular processes such as protein synthesis, nucleic acid metabolism including DNA synthesis, gene transcription [ 1 ], cell proliferation and differentiation, and mitosis [ 5 ].

These zinc-requiring cellular processes extend the significance of zinc to physiological level. For example, zinc is a structural component of the bone tissue and plays a role in collagen matrix synthesis, mineralisation, and bone turnover [ 6 ]. Also, zinc regulates intracellular signalling pathways of innate and adaptive immune cells [ 7 ], influences immune responses including antibody production, inflammatory signalling and lymphocyte differentiation [ 8 ], and thereby plays an essential role in the functionality of the immune system.

Zinc also plays a role in the endocrine system. For example, zinc is required in the formation and structural stability of insulin [ 9 ]. Essentially, insulin dimers form hexameric units, coordinated by two zinc ions in the central axis of the hexamer [ 10 ]. No wonder the beta cells of the pancreas contain significantly higher concentrations of zinc than other cells of the body. Furthermore, zinc ions act on the insulin signalling pathway and stimulate lipogenesis and glucose uptake into the adipocytes [ 9 ]. Zinc transporter (ZnT)-8 mediates signalling between the pancreas and liver to allow optimal insulin release, while zinc/iron-regulated-transporter-like-protein-(ZIP)7 is thought to play a role in glycaemic control within skeletal muscle. [ 9 ].

Thyroid hormones are involved in many physiological functions, such as the anabolism of proteins and increasing the basal metabolic rate and bone growth in children [ 11 ]. Zinc plays an important role in the metabolism of thyroid hormones. It regulates the synthesis of thyroid-releasing hormone (TRH) and thyroid-stimulating hormone (TSH). Zinc modulates their structure and thereby regulates the transcription factors which are essential for thyroid hormone synthesis [ 12 ]. Thus, in humans with zinc deficiency, levels of TSH, serum triiodothyronine (T3) and thyroxine (T4) also decrease [ 13 ], with several studies suggesting zinc deficiency as a cause of subclinical hypothyroidism [ 14 ]. Unsurprisingly, zinc supplementation appears to enhance thyroid hormone levels, particularly T3 [ 15 ].

Zinc is essential for male fertility. A zinc-sensing receptor, known as GPR39, has been found in the sperm tail and acrosome. When extracellular Zinc(II) binds to this receptor, it triggers an intracellular signalling pathway that ultimately results in increased sperm motility and acrosomal exocytosis [ 16 ]. Thus, zinc could have a role in the prevention, diagnosis and treatment of male infertility [ 17 ].

Additionally, zinc is important for the normal development and functioning of the central nervous system (CNS). Zinc balance is vital for neural tube formation and stem cell proliferation during development. Various zinc-dependent enzymes contribute to the function of the CNS, and ‘free’ zinc appears to modulate a variety of post-synaptic receptors. For example, zinc inhibits GABA-A receptors, which reduces their inhibitory actions. Alterations in zinc levels thereby affect the CNS and play a role in conditions such as Alzheimer’s disease and depression [ 18 ].

The human retina contains zinc in high concentrations [ 19 ]. Studies have suggested a link between higher anti-oxidant intake, including zinc (likely because zinc is a cofactor of superoxide dismutase, an anti-oxidant enzyme and also because zinc is an inhibitor of NADPH oxidase [ 20 ], which catalyses the production of reactive oxygen species [ 21 ]) and a decreased risk of age-related macular degeneration (AMD) [ 22 ], a leading cause of vision loss [ 23 ]. Studies have proposed the benefits of anti-oxidant supplementation, including zinc, in slowing the progression of AMD through the prevention of cellular damage in the retina [ 24 ].

Importantly, randomised trials in children six months to twelve years of age showed a positive effect of zinc supplementation in reducing all-cause and infectious disease mortality. It also showed a minor positive impact on linear growth [ 25 ].

Collectively, these examples highlight the significance of zinc in human health.

Micro-deficiencies and prevalence of zinc deficiency

It is estimated that 372 million (56%) preschool-aged children and 1.2 billion (69%) non-pregnant women of reproductive age across the globe have a deficiency in at least one of the micronutrients, namely zinc, folate, vitamin A and iron. Geographically, 75% of micronutrient-deficient preschool-aged children live in South Asia, sub-Saharan Africa, or East Asia and the Pacific. 57% of micronutrient-deficient non-pregnant women of reproductive age live in East Asia and the Pacific or South Asia [ 26 ]. An estimated 17% of the world’s population is at risk of insufficient zinc intake [ 1 , 27 ]. In Southeast Asia and sub-Saharan Africa, zinc deficiency is endemic, affecting up to 33% of the population. Zinc deficiency is also prevalent in Turkey, Egypt, and Iran due to high phytate intake in their diets, which decreases zinc absorption and, therefore, its bioavailability. Other countries have a markedly lower prevalence of zinc deficiency, notably China, where its incidence decreased from 17 to 8%, as recorded in 2005 [ 1 ].

Zinc uptake, absorption, and regulators of its bioavailability

Zinc: location, dietary sources, and intake recommendation.

Table ​ Table1 1 provides an overview of the level and proportion of zinc at physiological and cellular levels in the human body.

Table 1

Zinc levels in a healthy human

*Conversion performed using MediCalc available at https://www.scymed.com/en/smnxtb/tbcbpgh1.htm

Zinc cannot be stored in substantial amounts, and so, regular dietary intake is essential to ensure sufficient zinc availability [ 17 ]. Dietary sources of zinc include fish, oysters, meat, legumes, nuts, beans, whole grains, beef, eggs, and dairy. Oysters are the richest source of zinc, while fruits and vegetables are the poorest source. Although beans, nuts, and whole grains contain zinc, the bioavailability of zinc from these is lower than food from animal sources due to the presence of phytates [ 37 ].

There are differences in the dietary recommendations of zinc. Data around this include recommendations of 7.4 mg/day (approximately) [ 38 ]. In the US, recommendations include 15 mg/day [ 30 ], 11 mg/day [ 39 ] and 11 mg/day and 8 mg/day for adult men and women, respectively, who are age 19 and above [ 37 ]. In the UK, the recommendation is 9.5 mg/day for an adult man and 7 mg/day for an adult woman. The UK Department of Health recommends that zinc intake should not exceed 25 mg/day [ 40 ].

Zinc transporters: ZIPs and ZnTs

During digestion, zinc is released from food as free Zn 2+ ions. These ions need to be transported from the intestinal lumen to the enterocyte, then from here into the circulation and from circulation to the cells that require zinc for their activities. Also, within cells, there is intracellular zinc movement and compartmentalisation. These zinc transport processes are facilitated by two important types of zinc transporters: Zinc/iron-regulated-transporter-like-proteins (ZIPs) and Zinc transporters (ZnTs). ZIPs increase intracellular/cytoplasmic zinc levels by transporting zinc from the extracellular space and/or intracellular organelles into the cytoplasm. In general, ZnTs (the exception is ZnT5B, which is a bidirectional transporter) reduce intracellular/cytoplasmic zinc by transporting zinc from the cytoplasm to extracellular space (promoting zinc efflux from cells) or into an organelle for its compartmentalisation [ 38 ]. ZnTs and ZIPs are located in several different tissues/cells, on different regions of the cell surface, and on the surface of intracellular organelles (Tables  2 and ​ and3 3 ).

Table 2

ZnT transporters: location and regulation

Table 3

ZIP transporters: location and regulation

Process of zinc uptake, absorption, and circulation

Zinc absorption/uptake primarily occurs in the proximal part of the small intestine, in the distal duodenum and proximal jejunum [ 39 ]. Zn 2+ ion entry into the enterocyte is mediated via ZIP4 and/or ZnT5B in the duodenum and jejunum (Fig.  1 ). Another transmembrane ion transporter potentially involved in zinc uptake into the enterocyte is Divalent Metal Transporter-1 (DMT-1) [ 29 ]. Regardless of the transporter used, once Zn +2 ions are in the enterocyte, ZnT1 transports zinc from the enterocyte into the portal blood [ 45 ]. From here, these ions travel through the hepatic portal vein, mostly likely bound to ligands such as amino acids and citrate [ 96 ]. A previous study in rats found that most zinc travels to the liver in portal blood bound to transferrin [ 97 ]. At the liver, the portal vein branches, and the blood drains through sinusoids [ 98 ]. Some zinc enters hepatocytes, most likely via ZIP14 [ 99 ]. After the blood passes through the sinusoids, it is directed to the central vein, then hepatic veins and eventually the systemic circulation [ 98 ]. From the systemic circulation, zinc ions are transported to various body tissues such as the in brain, muscle, and bone [ 100 ] (Fig. 1 ).

Zinc uptake under physiological conditions. Zinc ions are transported from the intestinal lumen into the enterocyte by ZIP4. Other zinc transporters on the apical membrane include ZIP8 [ 101 ], ZnT10 [ 67 ] and ZnT5B [ 56 ]. ZnT5B has a bidirectional transport function [ 56 ]. Transporters located on the basolateral membrane of the enterocyte include ZnT1 [ 44 ], ZIP14 [ 102 ] and ZIP5 [ 103 ]. ZnT1 transports zinc ions from the enterocyte into the portal vein. Zinc ions travel in the portal blood to the liver, most likely bound to citrate, amino acids [ 96 ] and transferrin [ 97 ]. At the liver, portal blood drains through sinusoids, from where some zinc is taken up by hepatocytes. The rest of the zinc joins the systemic circulation from where it can reach distant tissues such as the brain, muscle, and bone via their respective ZIP transporters. Figure created with BioRender.com

There is a wide consensus that, in the systemic circulation, the majority of zinc is bound to albumin, a lesser amount bound to α 2 -macroglobulin, and a fraction bound to amino acids. There is a debate over whether transferrin has a role to play as a zinc carrier in the systemic circulation. Some studies suggest it may play a role [ 28 , 29 ], whilst others state that transferrin does not have a primary role in the distribution of zinc [ 104 ].

Variability in data regarding the proportion of zinc bound to albumin and α 2 -macroglobulin in systemic circulation

There have been various propositions regarding the proportions of these zinc carriers, particularly albumin. While some stated 80–85% of zinc is bound to albumin [ 105 ], others stated that this figure is 60% (with the remaining 30% bound to α 2 -macroglobulin and 10% to transferrin) [ 29 ], or 70% [ 38 ], or 80% (with the remaining 20% bound to α 2 -macroglobulin) [ 28 ], and yet others believe that approximately 98% zinc in the systemic circulation is bound to albumin [ 106 ].

Regardless of the exact percentage, conditions affecting albumin concentration, such as liver cirrhosis, may affect serum zinc levels [ 38 ]. For example, patients with liver cirrhosis and hepatic encephalopathy show decreased serum zinc levels [ 107 ].

Binding of Zn +2 ions to the different ligands could be the reason for the concentration of “free” Zn +2 ions in the circulation to be low (~ 0.1–1.0 nM) [ 96 ].

Regulators of zinc bioavailability

Bioavailability is the fraction of intake that can be absorbed into the blood and can be used for physiological processes in the body. Studies suggest that the typical range of zinc absorption from the intestinal lumen into the circulation is 16–50% [ 29 ], with an average of around 33% [ 38 ].

An important factor affecting zinc bioavailability is the solubility of zinc in the intestinal lumen. Previously, it was proposed that amino acids released from protein digestion enhanced zinc absorption by increasing its solubility [ 108 ]. Recent reviews have suggested that protein levels in the diet positively correlate with zinc uptake, and the presence of animal-based protein enhances zinc absorption more than the presence of plant-based protein. However, it is still uncertain whether amino acids can enhance zinc bioavailability due to a lack of consensus among studies. Citrate is a low molecular weight ligand found in milk which is thought to have a positive effect on zinc bioavailability by forming zinc-citrate complexes, thereby enhancing zinc uptake. These complexes are found in higher concentrations in human milk than in cow’s milk. Therefore, zinc absorption from human milk is higher than cow’s milk [ 29 ]. Also, food fermentation and germination enhance zinc absorption by reducing the phytate content of food [ 108 ]. Essentially, fermentation and germination both promote endogenous phytase activity [ 109 , 110 ]. Germination also facilitates de novo synthesis of phytases, enzymes which hydrolyse phytic acid [ 110 ].

On the other hand, several inhibitors decrease zinc solubility and, thereby, its bioavailability, for example, phytic acid/phytates found in food such as legumes, beans, and nuts. Phytates bind to zinc in the intestine, form insoluble complexes and thereby limit zinc absorption. Thus, zinc bioavailability from plant-based foods is lower than foods from animal sources [ 37 ]. Calcium and casein in cow’s milk may also reduce the bioavailability of zinc [ 25 ].

In addition, some medications may reduce serum zinc levels. For example, long-term use of distal-tube diuretics such as chlortalidone may result in significant zinc depletion due to increased urinary zinc excretion (hyperzincuria) [ 111 ]. Angiotensin-converting enzyme inhibitors (ACEis) or angiotensin-receptor blockers (ARBs), commonly used to treat heart failure, may cause zinc deficiency [ 112 ]. Also, when consuming or prescribing oral zinc supplements for zinc deficiency, interactions of medications must be carefully monitored. For example, orally consumed zinc may decrease the absorption of many orally taken drugs, such as alendronate and risedronate, which are used to prevent and treat osteoporosis. Similarly, zinc can inhibit the absorption of many antibiotics such as ciprofloxacin and doxycycline [ 113 ].

Zinc homeostasis at physiological level

At the physiological level, zinc homeostasis is primarily maintained by controlling zinc absorption and excretion. Of the zinc that is excreted from the body, ~ 50% is lost via faeces [ 38 ] (including zinc in sloughed epithelial cells) [ 28 ], and the rest is lost through urine, sweat, menstrual flow, semen, loss of hair and nails, and shedding of skin [ 29 ]. The zinc absorption mechanism adapts more slowly, while zinc excretion mechanisms can alter quickly [ 29 , 38 ]. During zinc deficiency, absorption of zinc can be increased up to 90% [ 28 ] and faecal and urinal excretion of zinc is rapidly reduced [ 29 ]. Certain tissues, such as the bone marrow, liver, and testes, secrete zinc into the circulation as a response to zinc deficiency. Other organs such as skin, skeletal muscle, heart, and kidney conserve their zinc levels even in zinc-deficient states [ 114 ].

Endogenous zinc secretion

The process of endogenous zinc secretion into the intestinal lumen may play a role in maintaining zinc homeostasis [ 115 ]. There are many ways of mediating zinc secretion into the intestinal lumen, for example, via biliary, pancreatic and gastroduodenal secretions and sloughing of mucosal cells [ 56 , 114 , 116 ]. Zinc transport from the portal circulation into the enterocyte is mediated by ZIP5 and ZIP14 on the basolateral membrane of enterocytes. ZnT5B transporter on the apical membrane of enterocytes is a bidirectional transporter that can transport enterocyte zinc ions into the intestinal lumen and vice versa, thereby mediating both, enterocyte uptake and endogenous secretion of zinc [ 29 , 117 ].

In the context of zinc secretion into intestinal lumen from the exocrine secretions of the pancreas, there are several zinc transporters that participate in this process. For example, zinc ions are transported into the pancreas from the plasma via ZIP5. These ions are then transported into zymogen granules via ZnT2 and excreted into the digestive tract as pancreatic secretions. Interestingly, zinc concentration in pancreatic tissues and secretions is influenced by dietary zinc intake. Excess dietary zinc leads to upregulation of ZnT2 in acinar cells, and restriction of dietary zinc leads to reduced zinc concentration in both pancreatic tissue and secretions. Thus, zinc homeostasis is regulated by adjusting zinc excretion through the entero-pancreatic axis.

Regardless of the pathway, some zinc in the lumen is reabsorbed into the circulation through uptake via enterocytes. Thus, the balance between the absorption of dietary zinc, and the excretion and reabsorption of endogenous zinc collectively maintain zinc levels in the body [ 29 ].

Zinc homeostasis at the cellular level

Zinc concentration at the physiological level is determined by zinc regulation at the cellular level, which is determined by zinc transporters (Tables  2 and ​ and3). 3 ). Zinc transporters are regulated through various mechanisms, including activation of transcription, stabilisation of mRNA, modification of protein, trafficking to specific organelles, and transporter degradation. Regulatory stimuli include zinc, cytokines, hormones, endoplasmic reticulum stress, oxidative stress, and hypoxia [ 28 ].

Effect of high and low zinc on ZnTs: how zinc regulates ZnT expression

ZnT transporters are differentially regulated by zinc levels but with some similarities in mechanisms. Table ​ Table2 2 presents a detailed view of ZnTs, their cellular and tissue distribution, and the stimuli and mechanisms involved in the upregulation or downregulation of the ZnTs. Essentially, high zinc levels increased ZnT1 and ZnT2 mRNA expressions [ 44 ] but decreased ZnT10 mRNA levels [ 68 ]. Interestingly, ZnT5 expression is unique and complex because high or low zinc levels have been shown to increase or decrease its expression [ 43 ]. This could be due to the B variant of ZnT5, which has a bidirectional functionality in zinc transport [ 29 ].

Effect of high and low zinc on ZIPs: how zinc regulates ZIP expression

Table ​ Table3 3 details the ZIPs, and their cellular and tissue distribution, along with the stimuli and mechanisms involved in their upregulation or downregulation.

Most ZIP transporters were confirmed to increase their expression in response to low zinc levels including ZIP2 [ 74 ], ZIP3 [ 70 , 76 ], ZIP4 [ 44 ], ZIP10 [ 86 ], and ZIP14 [ 92 ], while only ZIP5 expression was found to decrease [ 71 ]. There is some uncertainty regarding ZIP transporter regulation in response to high zinc levels. For example, ZIP7 levels inversely correlated with cellular zinc levels in CLN6 neurons [ 81 ] implying that higher cellular zinc would lead to lower ZIP7 levels. However, a causal link is yet to be confirmed because this finding could be confounded by the presence of CLN6 disease. In another example, dietary zinc restriction led to decreased ZIP11 expression in the mouse stomach. However, upon dietary zinc repletion, ZIP11 expression levels were not restored. This suggests that ZIP11 may be unaffected by zinc excess and possibly downregulated by zinc deficiency [ 89 ]. This unresponsiveness to zinc (in the form of dietary zinc repletion) [ 89 ] is unexpected, given the presence of multiple metal-response elements (MREs) upstream of the first exon of the ZIP11 gene [ 44 ].

Other regulators of ZnTs and ZIPs

Zinc transporters respond to various stimuli other than zinc (Tables  2 and ​ and3). 3 ). For example, in the immune system, T-cell stimulation by phytohaemagglutinin decreases the mRNA expressions of ZnT1, ZnT4, ZnT6 and ZnT7 [ 47 ]. These observations reiterate the importance of zinc in modulating the immune response. Moreover, in dendritic cells, lipopolysaccharide stimulation during toll-like receptor signalling increased the mRNA transcripts of ZnT1, ZnT4 and ZnT6 but decreased those of ZIP6 and ZIP10 [ 46 ].

Cytokines (namely IL-6) are known to increase ZIP14 levels [ 59 ] but decrease ZnT10 levels [ 44 ]. Hormones such as glucocorticoid and prolactin can increase ZnT2 levels [ 44 ], while thyroid hormone can increase ZIP10 levels [ 88 ]. In addition, glucose was found to increase ZIP14 levels [ 94 ].

Metals other than zinc, such as manganese [ 67 ] and iron [ 91 , 95 ], can also regulate zinc transporters, which reflects their role in assisting general metal homeostasis. Interestingly, high manganese intake upregulated liver ZIP14 expression in male and female mice but upregulated ZIP14 expression in the small intestine of only male mice. ZnT10 expression was upregulated in the same regions but only in male mice [ 67 ]. These observations indicate that there might be sex-based differences in the regulation of zinc transporters.

Metallothioneins (MTs): at the interface of physiological and cellular zinc regulation

MTs are a family of proteins, ubiquitously expressed (in most cells and tissues), which have a high affinity for d10 electron configuration metals, including zinc and copper [ 118 ]. MT1 and MT2 are the main isoforms expressed in most adult mammalian tissues. MT3 has been identified in the brain, kidney, breast, pancreas, intestine, and bladder. MT4 has been reported in stratified squamous epithelium around the body and plays an important role in cell differentiation [ 119 ].

MTs are thought to play a key role in the systemic regulation of trace elements, including that of zinc [ 35 , 118 ]. To execute this function, MTs within the enterocyte exhibit their regulatory effect at the absorption stage. Here, MTs can bind to zinc ions within the enterocyte cytoplasm and thereby reduce the availability of free intracellular zinc. Also, when zinc is needed by the cell, MTs can unbind zinc ions and make zinc available. So, if enterocyte zinc concentration is high, then MTs can bind to intracellular zinc and reduce free zinc ions [ 120 , 121 ]. Consequently, this would reduce the amount of zinc exported into the portal blood, which, in turn, would reduce the amount of zinc distributed around the body. MTs are also thought to mediate zinc trafficking within the cell and zinc transfer to zinc transporters. Thus, through their zinc buffering and muffling properties, MTs help in maintaining zinc homeostasis [ 29 ].

Acquired zinc deficiency: diagnosis and treatment

Acquired zinc deficiency could be due to insufficient intake (seen in anorexia nervosa), increased loss (seen in chronic diarrhoea or burns patients), increased requirement (seen in pregnant and breastfeeding individuals) or malabsorption (seen in Crohn’s disease [ 1 ] and coeliac disease [ 122 ]). It shows clinical features like diarrhoea, frequent infections, and skin lesions. However, these patients usually present the symptoms later in life alongside the aforementioned factors [ 123 ]. Due to overlap of symptoms, other differentials that should be considered whilst diagnosing zinc deficiency include: depression, hypothyroidism, vitamin (A, B12 and D) deficiencies, and iron deficiency [ 1 ].

Mild zinc deficiency can manifest clinically with serum values ranging from 40 to 60 µg/dL [ 124 ]. It has been suggested that acquired zinc deficiency can be diagnosed by a simple blood test showing fasting serum zinc < 70 µg /dL. Furthermore, since low albumin levels can cause low zinc levels, serum albumin levels should also be measured [ 125 ].

Some suggest that plasma zinc as a biomarker is non-specific, and it is difficult to develop a single biomarker of zinc status due to zinc’s diverse functions [ 25 ]. However, taking a fasting sample in the morning, separating plasma or serum from cells within 45 min and using zinc-free vacuum tubes can improve accuracy [ 1 ]. In general, urinary zinc levels are not a useful diagnostic parameter for zinc deficiency, whereas hair zinc levels are useful only in the context of chronic deficiency [ 1 , 126 ]. In addition to laboratory investigations, the clinical aspects comprising patient risk factors, geographical prevalence, and age of presentation, alongside physical examination and an appropriate history-taking, can help to establish the diagnosis [ 1 ].

Oral zinc supplementation, such as zinc gluconate for either short-term or long-term depending on the underlying aetiology, is usually used to cure the acquired deficiency [ 1 ]. Interestingly, zinc supplements can be formulated as zinc oxide or as salts with acetate, gluconate and sulphate [ 2 ]. A clinical trial reported that zinc oxide administered without food is less well absorbed than other zinc formulations as it is more insoluble [ 127 ]. Zinc citrate has a relatively higher zinc content, yet this is countered by the finding that zinc absorption in the form of citrate does not differ from that of zinc gluconate. However, the affordability of zinc citrate may make this an attractive alternative to zinc gluconate [ 127 ]. A potential complication of zinc deficiency treatment is overcorrection with zinc supplementation since this can cause acute zinc toxicity [ 1 ]

Other clinical conditions that may show low zinc levels are tabulated in Table  4 .

Table 4

Examples of clinical conditions that show low zinc levels

Inherited zinc deficiency acrodermatitis enteropathica: diagnosis and treatment

Many inherited defects of zinc deficiencies are known. Most cases are associated with mutations in the SLC39A4 gene on chromosome 8. This gene encodes the zinc transporter ZIP4 [ 134 – 136 ]. The pathological condition is referred to as acrodermatitis enteropathica, a rare autosomal recessive condition with the incidence of roughly 1 in 500,000 births [ 1 , 137 ]. It affects males and females equally [ 137 ]. Because ZIP4 mediates the transport of zinc ions from the intestinal lumen into the enterocyte, a mutation in the gene encoding ZIP4 does not allow zinc ions to be transported into the enterocyte through this transporter. Consequently, insufficient zinc ions reach the systemic circulation or distant tissues (Fig.  2 ) [ 29 ]. Although a small amount of zinc may be taken up via the passive paracellular route [ 138 ], the result is zinc deficiency.

Mechanisms/events underlying zinc deficiency due to mutation in ZIP4 (Acrodermatitis enteropathica). In acrodermatitis enteropathica, there is a mutation in the SLC39A4 gene which encodes the ZIP4 protein. Dysfunctionality in ZIP4 transporter causes limited zinc uptake by the enterocyte, and therefore, insufficient zinc transported into the portal vein via ZnT1. Insufficient zinc ions enter the liver and the systemic circulation, leading to less zinc reaching other tissues. The result is zinc deficiency, which can be life-threatening, if not treated promptly. Figure created with BioRender.com

Notably, while ZIP4 has two zinc-binding sites and thereby can show increased efficiency in capturing and delivering zinc to the enterocytes, how ZnT5B (another zinc importer on the enterocyte) transports zinc ions into the enterocyte is not known [ 139 ]. It is conceivable that ZnT5B may have a lower affinity to zinc ions than ZIP4, and therefore, although it can allow the entry of zinc ions into the enterocyte, it cannot compensate for ZIP4 dysfunction. Left untreated, acrodermatitis enteropathica is fatal within the first few years of life [ 125 ]

Acrodermatitis enteropathica patients usually manifest symptoms early in life [ 1 ] in the phase of weaning from breastfeeding [ 140 ]. Symptoms include a triad of alopecia, diarrhoea, and dermatitis [ 141 ]. Patients may also show growth impairment, psoriasiform lesions (well-defined scaly plaques most often found on the elbows) and frequent infections [ 1 ]. Alongside the consideration of clinical symptoms, serum zinc level < 70 µg/dL in fasting and low serum alkaline phosphatase may be suggestive of acrodermatitis enteropathica [ 125 ]. Note that alkaline phosphatase is a zinc-dependent enzyme [ 142 ]. Molecular genetic testing can identify SLC39A4 mutation and confirm acrodermatitis enteropathica.

Treatment involves zinc supplementation, but the formulation of zinc depends on the route of administration. For example, zinc gluconate and sulphate [ 1 ] are commonly used orally, while zinc chloride is preferred parenterally [ 125 ]. Treatment is lifelong with patient compliance being crucial [ 40 ].

Another genetic cause of acrodermatitis enteropathica is due to a mutation in the SLC30A2 gene of the breastfeeding mother. This gene encodes for ZnT2, a zinc transporter expressed in the mammary glands [ 143 ]. In secreting mammary epithelial cells, ZnT2 imports zinc into vesicles, mediating zinc secretion into the breast milk. A mutation in this gene results in decreased zinc secretion into the breast milk. This can lead to severe zinc deficiency in exclusively breastfed infants [ 44 ]. This can be treated by supplementation of zinc at 5 mg per day whilst breastfeeding. After weaning, no further action is needed [ 143 ]. Most paediatric patients with acrodermatitis enteropathica do not present with the classic triad of periorificial and acral dermatitis, diarrhoea, and alopecia. Less than one-third of paediatric patients present in this way. Common presentations in children include recurrent infections, irritability, behavioural changes, neurological disturbances, and failure to thrive [ 140 ].

ZIP8 mutations result in cortical atrophy and, consequently, intellectual disability in the affected patient. A mutation in the SLC39A14 gene (encoding ZIP14) can lead to parkinsonism-dystonia in children [ 144 ], whilst a mutated ZIP13 protein is responsible for the spondylocheirodysplastic form of Ehlers-Danlos syndrome [ 145 ]. In mice, ZIP7 knockout was lethal, whilst a morpholino knockdown of ZIP7 caused neurodevelopmental issues in zebrafish [ 144 ].

Zinc toxicity: diagnosis and treatment

To our knowledge, there have been no reports on zinc overload/toxicity due to mutations in zinc transporters. The reported cases of zinc toxicity are due to acquired causes rather than inherited ones. Causes include pesticide exposure and exposure to compounds used to make paints, rubber and dyes [ 40 ].

The tolerable upper intake level of zinc, according to the US Institute of Medicine, is as follows: 4 mg in youngest infants, 12 mg in children 4–8 years old, 34 mg in adolescents (14–18 years), and 40 mg for persons aged 19 or older [ 146 ]. Acute and chronic zinc toxicities are defined as zinc intake of more than 200 mg/day and 50–150 mg/day, respectively [ 40 ]. Acute zinc toxicity is likely due to excessive zinc supplementation as opposed to excessive dietary zinc intake. Longer-term causes of zinc toxicity include occupational exposure to zinc [ 147 ] and iatrogenic causes such as overprescribing of zinc-containing medication, zinc present in dental fixtures (though modern preparations in the UK and US are now zinc-free) and overconsumption of over-the-counter zinc supplements [ 148 ].

At zinc doses higher than 50 mg/day, symptoms such as nausea, diarrhoea and abdominal discomfort may occur, whilst doses higher than 150 mg/day can adversely affect the body’s lipid profile and immune system. On the other hand, it has been suggested that symptoms of zinc toxicity may not manifest until intake exceeds 1–2 g [ 30 ]. The most common cause of zinc excess is taking too many zinc supplements [ 149 ]. Chronic zinc toxicity can lead to disturbances in copper metabolism causing low copper status, which affects iron distribution and causes anaemia, red blood cell microcytosis, neutropenia and reduced immune function [ 150 , 151 ].

Zinc toxicity presents in different ways depending on the mode of zinc overload. For example, acute dietary ingestion presents as nausea, vomiting, diarrhoea, and muscle cramps. If toxicity is caused by inhalation of fumes, it presents with flu-like symptoms such as cough, fever, and chills. Chronic ingestion slowly leads to a syndrome of neuropathy, anaemia, fatigue, and spasticity. The 2017 Annual Report of the American Association of Poison Control Centres’ (AAPCC) National Poison Data System (NPDS) reported 1236 cases of exposure to zinc compounds, most of which were unintentional exposures in children less than five years of age. There were no deaths or major adverse health events as a consequence of this though [ 30 ].

An investigation to diagnose zinc poisoning includes several aspects like a thorough history to gain an understanding of the mode of overload, levels of serum zinc, copper and ceruloplasmin, liver function tests, platelet count, and chest X-ray. Treatment for acute ingestion involves anti-emetics, fluids and proton pump inhibitors [ 30 ]. Treatment for metal fume inhalation focuses on oral rehydration, anti-pyretics and supplemental oxygen with bronchodilators [ 152 ]. In chronic zinc toxicity, first the identification and then the removal of the source of zinc is essential. This can be followed by treatment with copper sulphate [ 30 ]. This treatment works because copper competes with zinc for absorption, so exogenous copper intake reduces zinc absorption [ 1 ]. Very severe cases may require zinc chelation with agents such as diethylenetriamine pentaacetate (DTPA) [ 30 ].

Zinc-induced copper deficiency (ZICD)

An important complication of chronic zinc toxicity is zinc-induced copper deficiency (ZICD). Excess zinc levels in the small intestine stimulate increased expression of MTs in the enterocytes. Since copper has a greater affinity for MTs compared to zinc, copper outcompetes zinc for MT binding sites, and consequently, the copper bound to MT is excreted via sloughing of enterocytes. This results in decreased absorption of copper and, therefore, copper deficiency [ 153 ]. The co-existence of hyperzincaemia (high zinc in serum) and hypocupraemia (low copper in serum) is suggestive of ZICD [ 154 ]. Measurements of urinary zinc can be useful in the diagnostics of ZICD because urinary zinc levels are usually high in this condition [ 155 ].

ZICD tends to develop slowly over many months or years, although this apparent slow onset may be due to delayed diagnosis [ 155 ]. Early manifestation includes neutropenia, leukopenia and anaemia [ 154 ]. This anaemia is likely due to the disruption of copper’s physiological role in the differentiation of haematopoietic stem cells as well as intestinal iron absorption [ 156 ].

Under physiological conditions, copper plays a vital role in the synthesis and stabilisation of myelin, and in several enzymatic pathways required for the functioning of the nervous system. Therefore, if ZICD is left undiagnosed, it can lead to severe and permanent neurological complications including gait disturbances, paraesthesia and myelopathy [ 156 ].

One study highlighted that the over-prescription of zinc was a significant cause of ZICD. This shows that zinc can have potentially serious side effects, and it is not a harmless agent that can be prescribed without a strong justification [ 155 ]. Removal of the source of excess zinc along with oral copper gluconate treatment is often sufficient to revert anaemia, neutropenia and leukopenia seen in ZICD. Neurological deficits may also improve with this treatment; however, many never fully recover and will be left with permanent neurological deficits [ 156 ].

Trace elements play an important role in human health and disease. For example, the role of iron in various diseases, including liver fibrosis, alcohol-related liver disease, and COVID-19, has been reviewed [ 157 – 160 ].

Zinc is an essential micronutrient which cannot be stored in significant amounts, so regular dietary intake is vital. There does not seem to be a clear consensus on the recommended zinc intake, where the recommendation ranges from 7.4 to 15 mg/day. Citrate and food processing such as fermentation and germination, can enhance zinc uptake. It is unclear whether amino acids enhance zinc uptake. Phytic acid, found in cereals, legumes, and nuts, is known to decrease zinc bioavailability.

Zinc absorption occurs primarily in the proximal small intestine, where ZIP4 mediates zinc entry into enterocytes. ZnT5B and DMT-1 are also thought to play a role in this process. ZnT1 transports zinc from the enterocyte into the portal vein, via which zinc travels to the liver. Here, some zinc may enter the hepatocytes via ZIP14, and the rest may eventually drain into the systemic circulation for distribution to various bodily tissues. In the circulation, most zinc is bound to albumin, and the majority in the body can be found in skeletal muscle and bone.

Zinc deficiency can be inherited or acquired. The acquired form is due to insufficient intake, malabsorption, increased requirement, or excessive loss of zinc. Inherited zinc deficiency is mostly associated with mutations in the SLC39A4 gene (which encodes for ZIP4), resulting in a triad of alopecia, diarrhoea and dermatitis in a condition known as acrodermatitis enteropathica. In both inherited and acquired deficiencies, oral zinc supplementation is the mainstay of treatment with an excellent prognosis.

Zinc toxicity is only known to be acquired, not inherited, and may be acute or chronic. Symptoms include nausea, diarrhoea and abdominal discomfort but may vary depending on the mode of overload. Treatment involves the chelation of excess zinc using drugs.

Recommendations for future work

This review helped us identify the knowledge gaps in the literature on zinc. For example, there is no clear consensus on the proportion of zinc that is bound to albumin in the systemic circulation. Albumin levels decrease in several conditions, including liver cirrhosis, and so, knowledge of the proportion of zinc bound to albumin may inform alternative or supplementary treatments for those with albumin-depletion-induced zinc deficiency. In such patients, only oral zinc supplementation may not be enough to resolve the deficiency because there is an insufficient level of the zinc carrier albumin to distribute zinc around the body. Should albumin be the predominant zinc carrier in the circulation, albumin supplementation may play an important role in treating zinc deficiency. There are some other uncertainties in the context of zinc carriers. For example, there are contrasting suggestions on whether transferrin has a role to play as a zinc carrier in the systemic circulation or not. Thus, the knowledge on zinc carriers will aid in our understanding of the pathogenesis of zinc-related conditions.

Another knowledge gap exists in the mechanisms by which the levels of certain zinc transporters increase or decrease in cells in response to a stimulus, as reflected in Tables  2 and ​ and3. 3 . Dedicated studies are required to elucidate these mechanisms as this might help devise ways of altering zinc levels within cells in a tissue-specific manner and thereby help ameliorate a zinc-related diseased state. Also, while our knowledge so far indicates that zinc toxicity is not caused by mutations in zinc transporters, examining genetics as a predisposing factor in the development of zinc toxicity might be helpful, as it has been in the case of zinc deficiency. Given the multi-faceted physiological role of zinc, such studies would improve the diagnostics and therapeutics of a range of conditions, positively impacting the health of the general population as well as of those with zinc-related diseases.

Acknowledgements

This article is made open access with the financial support of King’s College London, UK. Thanks to Najma Ali (GKT School of Medical Education, Faculty of Life Sciences and Medicine, King’s College London, UK) for providing some data that acted as a reference for writing a couple of paragraphs.

Author contributions

LIS contributed to primary investigation and writing-original draft; KF contributed to further literature search, analysis, and interpretation of data; and KJM contributed to conceptualisation, supervision, writing and editing.

No funding was accessed/obtained for writing this review.

Declarations

Authors declare that they have no competing or financial interests to disclose.

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Occurrence, uses, and properties

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• National Center for Biotechnology Information - PubChem - Zinc
• Lenntech - Zinc - Zn
• Harvard T.H. Chan School of Public Health - The Nutrition Source - Zinc
• U.S. Department of Health & Human Services - National Institutes of Health - Zinc
• Geology.com - Uses of Zinc
• Royal Society of Chemistry - Zinc
• Healthline - Zinc: Everything You Need to Know
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• Oregon State University - Linus Pauling Institute - Zinc
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• Table Of Contents

zinc (Zn) , chemical element , a low-melting metal of Group 12 (IIb, or zinc group ) of the periodic table , that is essential to life and is one of the most widely used metals . Zinc is of considerable commercial importance.

A little more abundant than copper , zinc makes up an average of 65 grams (2.3 ounces) of every ton of Earth ’s crust. The chief zinc mineral is the sulfide sphalerite (zinc blende), which, together with its oxidation products smithsonite and hemimorphite , constitute nearly all of the world’s zinc ore . Native zinc has been reported from Australia , New Zealand , and the United States , and the leading early 21st-century producers of zinc are China , Australia and Peru . For zinc’s mineralogical properties, see native element .

Zinc is an essential trace element in the human body , where it is found in high concentration in the red blood cells as an essential part of the enzyme carbonic anhydrase , which promotes many reactions relating to carbon dioxide metabolism . The zinc present in the pancreas may aid in the storage of insulin . Zinc is a component of some enzymes that digest protein in the gastrointestinal tract . Zinc deficiency in nut-bearing and fruit trees causes such diseases as pecan rosette, little leaf, and mottle leaf. Zinc functions in the hemosycotypsin of snails ’ blood to transport oxygen in a way analogous to iron in the hemoglobin of human blood.

Metallic zinc is produced by roasting the sulfide ores and then either leaching the oxidized product in sulfuric acid or smelting it in a blast furnace. Zinc is won from the leach solution by electrolysis or is condensed from the blast furnace gas and then distilled of impurities. For specific information on the mining, recovery, and refining of zinc, see zinc processing .

The major uses of zinc metal are in galvanizing iron and steel against corrosion and in making brasses and alloys for die-casting . Zinc itself forms an impervious coating of its oxide on exposure to the atmosphere, and hence the metal is more resistant to ordinary atmospheres than iron and corrodes at a much lower rate. In addition, because zinc tends to oxidize in preference to iron, some protection is afforded the steel surface even if some of it is exposed through cracks. The zinc coating is formed either by hot-dip galvanizing or electrogalvanizing.

Hot-dip galvanizing is the most common procedure for coating steel with zinc. This may be a batch process known as general galvanizing or a continuous coating of coils of steel strip. In general galvanizing, steel is pickled in acid , treated with fluxing agents, and then dipped in a bath of molten zinc at about 450 °C (840 °F). Layers of iron-zinc alloy are formed on the surface and are topped with an outer layer of zinc. Objects so treated range from small nuts and bolts to steel window frames and large girders used in construction. An ordinary grade of zinc containing up to 1.5 percent lead is normally used in this process.

In electrogalvanizing , zinc is deposited on a steel strop in as many as 20 consecutive electrolytic coating cells. There are several successful cell designs; the simple vertical cell is discussed here to explain the principle. The strip, connected to the negative side of a direct current through large-diameter conductor rolls located above and between two cells, is dipped into a tank of electrolyte by a submerged sink roll. Partially submerged anodes , opposing the strip, are connected to the positive side of the electric current by heavy bus bars. Zinc cations (i.e., positively charged zinc atoms ) present in the electrolyte are converted by the current into regular zinc atoms, which deposit on the strip. The bath is supplied with zinc cations either by zinc anodes, which are continuously dissolved by the direct current, or by zinc compounds continuously added to the electrolyte. In the latter case the anodes are made of insoluble materials, such as titanium coated with iridium oxide. The electrolyte is an acidic solution of zinc sulfide or zinc chloride with other bath additions to improve the quality of the coating and the current efficiency . Coating thickness is easier to control than in the hot-dip process because of the good relationship between electrical current and deposited zinc.

The negative electrode (outside can) in one common type of electric dry cell is composed of zinc. Another important series of alloys are those formed by the addition of 4 to 5 percent aluminum to zinc; these have a relatively low melting point but possess good mechanical properties and can be cast under pressure in steel dies. Considerable quantities of zinc in the rolled form are used for roofing, particularly in Europe; small additions of copper and titanium improve creep resistance —i.e., resistance to gradual deformation.

Freshly cast zinc has a bluish silver surface but slowly oxidizes in air to form a grayish protective oxide film. Highly pure zinc (99.99 percent) is ductile; the so-called prime western grade (99.8 percent pure) is brittle when cold but above 100 °C (212 °F) can be rolled into sheets that remain flexible. Zinc crystallizes in the hexagonal close-packed structure. When iron and zinc together are exposed to a corrosive medium, they constitute an electrolytic cell , and the zinc is attacked (oxidized to the Zn 2 + ion) preferentially because of its higher electrode potential. This so-called sacrificial protection, coupled with the much greater corrosion resistance of zinc under atmospheric conditions, is the basis for galvanizing .

Natural zinc is a mixture of five stable isotopes : 6 4 Zn (48.6 percent), 6 6 Zn (27.9 percent), 6 7 Zn (4.1 percent), 6 8 Zn (18.8 percent), and 7 0 Zn (0.6 percent).

• Transition Metal

Zinc and its importance for human health: An integrative review

• January 2013
• Journal of Research in Medical Sciences 18:144-157

• School of Public Health

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High meat diets enhance absorption ... Zn pool responsive to both hormones and diet ... High copper diets do not interfere with Zinc absorption. Iron ... – PowerPoint PPT presentation

• 1509, recognized as element
• Essentiality demonstrated
• Plants 1869
• Animals 1934
• Considered unlikely until 1955
• swine parakeratosis shown to be caused by Zn deficiency
• conditioned human deficiency demonstrated in 1956
• 1961, hypogonadal dwarfism suggested to be zinc deficiency
• 30th element in the periodic table (IIB element)
• MW 65.37, completely filled d orbitals
• In aqueous solutions
• One oxidation state, namely Zn2
• Prefers tetrahedral complex formation
• Not a redox active metal
• readily complexes with amino acids, peptides, proteins and nucleotides
• affinity for thiols, hydroxy groups ligands with electron-rich nitrogen donors
• Whole body 1.5g (female)-2.5g (male)
• Skeletal Muscle 57
• Kidneys 0.7
• Blood Plasma 0.1
• Relatively abundant mineral
• Good sources shellfish, beef and other red meats
• Slightly less good Whole-grains
• most in bran and germ portions
• 80 lost to milling
• phytates, hexa penta phosphates depress absorption
• P/Zn ratios of 10 or more
• Relatively good sources nuts and legumes
• Eggs, milk, poultry fish diets lower than pork, beef, lamb diets
• High meat diets enhance absorption
• 280g or 10 oz fits right into food pyramid guide
• cys met form stable chelate complexes
• Feed/Food source
• Phytate (calcium-phytate-zinc complex)
• Mainly hexa- and pentaphosphate derivatives
• Highly dependent on calcium
• Amino Acids
• histidine, cysteine
• Presence/Absence of other divalent cations
• Efficiency of absorption can vary from 15-60
• Under normal conditions 1/3 of dietary Zn is absorbed
• Zn status alters efficiency of absorption
• Uptake and retention is gt in growing animals
• Approximately 300 enzymes are associated with zinc
• Biological functions of Zn are divided into three categories
• Catalytic, Structural, Regulatory
• Role in metabolism
• Protein synthesis
• Nucleic acid metabolism
• Carbohydrate and energy metabolism
• Epithelial tissue integrity
• Cell repair and division
• Vitamin A and E transport and utilization
• Immune function
• Reproductive hormones
• Absorption takes place throughout the intestine
• Barrier? Storage site?
• Primarily in the jejunum
• Some absorption in the rumen
• No measurable amounts absorbed from stomach cecum or colon
• In small intestine
• Nonmediated (nonsaturable) process
• Not affected by dietary Zn intake
• Mediated (saturable) process
• Stimulated by Zn depletion
• Plasma contains approx .1 of the total zinc of the body
• Albumin is major portal carrier
• Binds to albumin by tetrahedral ligation to sulfur atoms
• 70 of Zn is bound to albumin in plasma
• 20-30 bound to a-2 macroglobulin
• Other plasma proteins
• Transferrin, histidine-rich glycoprotein, metallothionine
• Plasma Zn concns respond to external stimuli
• Intake fluctuations
• Acute stresses
• Plasma Zn levels do not influence absorption from mucosa
• Most reductions in plasma levels reflect increased hepatic uptake
• Hormonal control
• Rapidly cleared from plasma by liver
• Fast component of 2 pool model (T1/2 12.3 da)
• Single dose of zinc is taken up with T1/2 20 s
• Slow component, other tissues (T1/2 300 da)
• Bone and CNS uptake slow
• Pancreas, liver and kidney most rapid
• RBC muscle in between
• Exchangeable pool zinc status
• Hepatic uptake via a biphasic process
• Contribution to overall Zn flux
• Sequesters newly absorbed Zn
• Removes Zn from the circulation
• Saturable process initial step
• Temperature dependent
• Stimulated by glucocorticoids
• Linear accumulation subsequent step
• Does not require energy
• Erythrocytes
• Depends upon bicarbonate ions
• Fibroblasts, proximal tubule, lymphocyte
• Biphasic uptake (same as liver)
• Zinc transporters regulate Zn ion concentrations through import, export or sequestering Zn into vesicles
• Storage, toxicity
• 2 families exist
• ZnT- mainly exports Zn ions from cells
• ZIP important for Zn influx
• Number of transporters
• ZnT-1 all organs, small intestine (basolateral membrane), kidney (tubular cells), placenta
• ZnT-2 intestine, kidney, testis
• Efflux (?) intracellular vesicles
• ZnT-3 brain (synaptic vesicles) testis
• Influx, intracellular retention
• ZnT-4 mammary gland brain
• Efflux (into milk)
• Lethal mouse transgenic
• ZIP family transporters
• Responsible for influx of Zn as well as Mn2, Cd2, and other divalent cations into cells
• DCT1 duodenum, jejunum, kidney, bone marrow, others
• Non-specific Zn, Cd, Mn Cu actually have slightly higher affinity than Fe, the mineral for which the transport actions of this protein was first identified.
• Competition between Fe Zn Cu
• Storage sites
• No specfic storage sites are recognized
• Within cells, amounts sequestered within metallothionine could be considered as stores
• Anorexia, muscle catabolism, tissue zinc release
• Metalloenzymes cling tenaciously to zinc
• Serum/plasma zinc drops rapidly (1 week) with zinc deficient diet
• Zinc turnover is extensive and rapid
• Two-components of turnover, fast 12.3 days, and slow, 300 days
• Fast pool is also called the exchangeable pool
• Usually amounts to 157-183 mg Zn
• Lost via hair, sweat, desquamation, bile pancreatic secretions, seminal fluid, urine, feces
• Main endogenous loss
• Secretions into gut
• Bile and pancreas
• Mucosal cells
• Urinary and integumental losses
• lt 20 under normal conditions
• Losses increase with trauma, muscle catabolism, and administration of chelating agents (EDTA)
• Primarily in fecal material
• Unabsorbed Zn
• Secreted Zn (endogenous sources)
• From pancreatic and intestinal sources
• Metallothionein
• Concentrated in liver, kidney, pancreas, intestine
• Acts as a Zn2 buffer
• Controls free Zn2 level
• Control intracellular Zn pool responsive to both hormones and diet
• Zn-binding protein, metallothionein (MT), is involved in the regulation of Zn metabolism
• MT is inducible by dietary Zn via the metal response element (MRE) and MTF-1 mechanism of transcriptional regulation
• ? in cellular MT ? ? Zn binding within cells
• Acute infections associated with proinflammatory cytokines increses Zn uptake into liver, bone marrow and thymus and reduces the amount going to bone, skin and intestine
• Interactions of other divalent cations in the intestinal lumen
• ? Fe, ? Sn, ? Cd ? ? Zn
• ? Zn ? ? Cu
• High Zn diets reduce Cu absorption
• electronic configuration competition
• Metallothionine synthesis induced
• sequesters Cu in mucosal cell preventing serosal transfer
• Happens with 150mg Zn for two years
• Can be used with Wilsons disease patients
• High copper diets do not interfere with Zinc absorption
• Supplements inhibit zinc absorption
• Ferrous gt Ferric, heme no effect
• Pregnant and taking gt60mg Fe/day should also take Zn
• High Ca diets reduce Zn absorption
• effect enhanced in phytate rich diets
• not sure how much of a problem in humans
• post menopausal women yes, adolescent girls, no
• Tin (Sb), not usually high in diet, but diets high in Tin can increase fecal Zn excretion
• Cadmium (Cd), alter Zn distribution in body rather than altering absorption
• Folic acid, conjugase requires Zn
• High doses sometimes impair Zn status further in low Zn situation - mechanism currently unclear
• Zinc-containing enzymes
• More than 70 enzymes
• Secondary tertiary protein structures
• Metal stabilized active sites
• Examples of general types
• dehydrogenases
• phosphatases
• Cu/Zn Superoxide Dismutase
• General class of enzymes that protect against oxidative damage in the body.
• Zn important structurally
• Zn needed for insulin stored in pancreas
• Functionality drops rapidly so more of a working store than a static store
• Nuclear transcription factors (gt130)
• Same protein structural role forms zinc-fingers
• Zn-fingers bind DNA
• allow different nuclear hormones to interact with DNA via different DNA binding proteins
• up to 37 fingers have been found on a single transcription factor
• Vit. A, Vit. D, steroid hormones, insulin-like growth factor-1, growth hormone, and others bind to zinc-finger proteins to modulate gene expression
• Zn is responsible for thymidine incorporation
• Cell Differentiation
• Thymidine kinase activity
• Creatine kinase activity
• Transcription factors
• Regulate gene expression
• Involved in virtually all biological processes
• Development, differentiation, cell proliferation, response to external stimuli
• Consists of 2 domains
• DNA Binding Domain (DBD) recognizes and binds to specific DNA sequence elements in the promoter of target genes
• Protein-interacting Transactivation Domain (TAD) influences the rate of transcription
• Zinc finger proteins are characterized by their utilization of zinc ions as structural components
• C2H2 zinc finger binding motif
• Predominant motif in eukaryotic transcription
• Involved in skeletal differentiation
• Zinc binding motif is determined by the presence of 2 cysteine and 2 histidine residues that engage in a four coordinate bond with a singe Zn ion
• Bind to response elements in the upstream promoters of genes transcribed by RNA poly 2
• Binds to 5S ribosomal RNA gene, and 5S RNA, and activates transcription by RNA polymerase 3.
• Zinc Fingers
• Mutation c/ablation of binding
• in case of Zif268, loss in sequence-specific DNA binding that allowed viral infection
• Iron can replace Zn in fingers
• Low Zn and high Fe
• Fe gives rise to ROS more readily
• DNA damage carcinogenesis?
• Cadmium can replace Zn in fingers
• Non-functional, cytotoxic
• Gene expression is controlled by specific proteins call transcription factors
• Zinc containing transcription factors account for 1 of genome
• Zinc plays key structural role in transcription factor proteins
• Ligands for transcription factors include
• Thyroid hormones
• Membrane fractions contain high concentrations of Zn
• Increases rigidity of cell
• Protection from oxidative damage
• Competition for binding sites with redox metals
• In deficient animals
• Failure of platelet aggregation
• Due to impaired Calcium uptake
• Peripheral neuropathy
• Brain synaptic vesicles exhibit impaired calcium uptake
• Increased osmotic fragility in RBCs
• Decreased plasma membrane sulfhydryl concentration
• After Zinc depletion
• All functions within monocytes were impaired
• Cytotoxicity decreased in Natural Killer Cells
• Phagocytosis is reduced in neutrophils
• Normal function of T-cells are impaired
• B cells undergo apoptosis
• High Zn supplementation shows alterations in cells similar to Zn depletion
• Zn influences Vitamin A metabolism
• Absorption, transport, and utilization
• Vitamin A transport is mediated through protein synthesis
• Zn deficiency can depress synthesis of retinol-binding protein in liver
• Oxidative conversion of retinol to retinal requires Zn-dependent retinol dehydrogenase enzyme
• Retinol to retinaldehyde (retinal), for visual processes
• Night Blindness
• Hallmark deficiency sign for Vitamin A
• Seen with Zn deficiency as well, why?
• Stojanovic, Stitham and Hwa Critical Rose of Transmembrane segment Zn binding I the structure and function of rhodopsin JBC 279(34)35932-35941, 2004
• Rhodopsin proteins
• Excess accumulation within cells may disrupt functions of biological molecules
• Protein, enzymes, DNA
• Leads to toxic consequences
• Impaired copper availability
• Acute excessive intakes
• Local irritant to tissues and membranes
• GI distress, nausea, vomiting, abdominal cramps, diarrhea
• Relatively non-toxic
• Sources of exposure drinking water, feed, polluted air
• Growth retardation
• Delayed sexual maturation impotence
• Impaired testicular development
• Hypogonadism hypospermia
• Acroorifical skin lesions
• Other, glossitis, alopecia nail dystrophy
• Immune deficiencies
• Behavioral changes
• Night blindness
• Impaired taste (hypoguesia)
• Delayed healing of wounds, burns, decubitus ulcers
• Impaired appetite food intake
• Eye lesions including photophobia lack of dark adaptation
• Monogastric more susceptible
• Chickens pigs used to become deficient with high corn diets
• Old enemy phytate
• Ruminants resistant due to ability to break down phytates
• Increases urinary zinc excretion
• Can cause deficiency
• Poor intakes altered physiology
• Zn deficient rats failed to conceive
• Abnormalities of blastocyst development
• Offspring had high incidence of abnormalities
• Deformities of brain, skull, limbs, eyes, heart, lungs
• Low Zn intake during the third trimester may not have such profound effects
• Main stages of differentiation are already complete
• Can result in low birth weight, and prolonged and difficult parturition
• Factors that decrease plasma Zn concentration
• Bacterial endotoxins
• IL-1 causes increased Zn uptake by liver thymus and bone marrow
• Severe trauma or death can result from Zn supplementation to stressed animals
• Infants UL(x)
• 0-6 mo 2 mg/d AI (4)
• Children adolescents
• 7mos-1 yr 3 mg/d (5)
• 1-3 yrs 3 mg/d (7)
• 4-8 yrs 5 mg/d (12)
• 9-13 yrs 8 mg/d (23)
• 14-18 yrs (34)
• Males 11 mg/da
• Females 9 mg/da

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• Review Article
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• Published: 03 January 2024

Cellular zinc metabolism and zinc signaling: from biological functions to diseases and therapeutic targets

• Bonan Chen   ORCID: orcid.org/0000-0002-2430-7934 1 , 2 , 3   na1 ,
• Peiyao Yu 4   na1 ,
• Wai Nok Chan 1 , 2 , 3 ,
• Fuda Xie 1 , 2 , 3 ,
• Yigan Zhang 5 ,
• Li Liang 4 ,
• Kam Tong Leung   ORCID: orcid.org/0000-0002-7695-2513 6 ,
• Kwok Wai Lo   ORCID: orcid.org/0000-0002-3488-6124 1 ,
• Jun Yu   ORCID: orcid.org/0000-0001-5008-2153 2 , 7 ,
• Gary M. K. Tse 1 ,
• Wei Kang   ORCID: orcid.org/0000-0002-4651-677X 1 , 2 , 3 &
• Ka Fai To   ORCID: orcid.org/0000-0003-4919-3707 1 , 2  

Signal Transduction and Targeted Therapy volume  9 , Article number:  6 ( 2024 ) Cite this article

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• Cancer therapy
• Cell biology
• Tumour angiogenesis

Zinc metabolism at the cellular level is critical for many biological processes in the body. A key observation is the disruption of cellular homeostasis, often coinciding with disease progression. As an essential factor in maintaining cellular equilibrium, cellular zinc has been increasingly spotlighted in the context of disease development. Extensive research suggests zinc’s involvement in promoting malignancy and invasion in cancer cells, despite its low tissue concentration. This has led to a growing body of literature investigating zinc’s cellular metabolism, particularly the functions of zinc transporters and storage mechanisms during cancer progression. Zinc transportation is under the control of two major transporter families: SLC30 (ZnT) for the excretion of zinc and SLC39 (ZIP) for the zinc intake. Additionally, the storage of this essential element is predominantly mediated by metallothioneins (MTs). This review consolidates knowledge on the critical functions of cellular zinc signaling and underscores potential molecular pathways linking zinc metabolism to disease progression, with a special focus on cancer. We also compile a summary of clinical trials involving zinc ions. Given the main localization of zinc transporters at the cell membrane, the potential for targeted therapies, including small molecules and monoclonal antibodies, offers promising avenues for future exploration.

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Introduction.

As an crucial trace element, zinc is critical for numerous biological functions, and its imbalance has been linked to a variety of pathologies, including cancer. 1 , 2 Understanding the intricacies of zinc metabolism at the cellular level, including encompassing the absorption, intracellular trafficking, utilization, storage, and expulsion of zinc, can shed light on the various effects of zinc in cell physiology and pathology. 3 Zinc, an essential component in the regulation of cellular homeostasis, is receiving increasing attention for its role in cancer. 4 , 5

Significantly, an extensive body underscores the crucial role of zinc homeostasis across various biological systems. Zinc is estimated to bind to around 3000 proteins in vivo, representing about 10% of the human proteome, 6 with over 3% of genes in human bodies encoding proteins containing zinc finger domains. Consequently, zinc assumes a pivotal position during numerous physiological processes, including cell cycle progression, 7 , 8 , 9 immune functions, 10 meiosis, 11 and many other physiological procedures. Intracellular zinc metabolism and zinc signaling are exceptionally precise. Cytoplasmic free zinc concentration remains within the picomolar range, while the overall zinc level is estimated to be about 200–300 μM. 12

Cellular zinc homeostasis is delicately regulated by a network of proteins, which includes the solute carrier (SLC) families SLC30 (ZnT) and SLC39 (Zrt- and Irt-like proteins/ZIP), as well as the zinc-binding (MTs). 2 , 13 These proteins are crucial in the maintenance of cellular zinc homeostasis. Traditionally, two transporter family members operate opposite directions to achieve this equilibrium. The SLC30 family, encoding ZnT proteins, facilitates zinc efflux through translocating zinc from the cytoplasm to the lumen of organelles or the extracellular space. 1 Conversely, the SLC39 family, also known as the ZIP family, functions in zinc influx, transporting zinc into the cytoplasm from the extracellular space of the cell or the intracellular storage compartment, effectively elevating zinc levels. 14 Meanwhile, MTs majorly handle zinc storage within the cell, safeguarding against potential toxicity while ensuring availability when required. 13 Increasingly, cellular zinc metabolism has been linked to disease progression. This review will explore the potential role of cellular zinc metabolism in biology, tumorigenesis, and drug applications.

Regulation of cellular zinc signaling

Zinc distribution.

Zinc is prevalent in various human tissues. Adults typically possess a zinc content ranging from 1.4 to 2.3 g. 15 Approximately 85% of zinc resides in the muscles as well as the bones. Besides, about 11% of zinc is in the skin and liver. The remaining 4% of zinc was scattered in other tissues. 16 Notably, the maximum zinc concentration has been found in the retina and choroid of the eye. 17 Additionally, zinc is found in considerable amounts in the prostate, bones, liver, and kidneys. 18

Notably, most of the zinc is intracellular. Approximately 30–40% of the content resides in nuclei of cells, with approximately half distributed across the cytosol, organelles, and specific vesicles, while the remaining zinc is associated with cell membranes. 19 Based on current research, the total pool of zinc, encompassing both intracellular and extracellular compartments, can be distinguished into three distinct categories. 20 , 21 Firstly, the term “Immobile zinc” refers to zinc that is firmly bound to metalloproteins or metalloenzymes, serving as either a structural component or a cofactor. This form of zinc is stable and non-reactive. Secondly, “Mobile reactive zinc” or “labile zinc” is loosely associated with low molecular weight ligands and MTs. This form is exchangeable and reactive. Notably, this mobile form constitutes about 5% of all intracellular zinc, playing a pivotal role in zinc transfer reactions and signaling processes. 22 , 23 Lastly, the “free zinc” pool is another reactive form of the element. In mammalian cells and in extracellular fluids, however, the concentration of this zinc is quite low, with values oscillating between roughly 5 pM and 1 nM. 24

MTs, colloquially referred to as “zinc storage,” maintain intracellular free zinc levels through their interaction with cysteine. 25 , 26 In addition to MTs, members of the zinc transporter family, including ZIPs and ZnTs, play a critical role in managing zinc homeostasis. Remarkably, the cellular zinc transport activity of ZnT7 is crucial for regulating the localization of ERp44 within the Golgi apparatus, a specific subcellular organelle. 27 Notably, many secretory enzymes obtain essential cellular zinc in the Golgi complex. Moreover, as a molecular chaperone acting in the early secretory pathway, ERp44 can bind to zinc to control the protein binding and release, thereby managing protein transport and stability.

In recent times, the essential and multifaceted function of zinc as a signaling molecular has attracted significant attention. The generation of zinc signals arises from three main sources: vesicular exocytosis, zinc transport facilitated by zinc transporters for entry or exit from the cell or organelle, and the binding or dissociation of MTs with zinc. These aspects will be expounded upon in the subsequent sections.

Intracellular zinc signaling

The total concentrations of zinc in cells range from 200–300 μM, 12 whereas the eukaryotic labile (“free”) zinc concentration is in the picomolar range, as mentioned earlier for each specific cell type. 24 Notably, the cytoplasm contains minimal free zinc since intracellular zinc is mainly sequestered in organelles like the ER, Golgi apparatus, and mitochondria, the so-called zinc store. 28 Growing evidence suggests that zinc functions not only as a neurotransmitter for cell-to-cell communication but also as an intracellular signaling molecule, facilitating the transduction of various signaling cascades in response to extracellular stimuli. This has led to the concept of zinc as the “calcium of the 21 st century”. 29

As previously mentioned, there are two pathways for intracellular zinc ion release, namely from intracellular zinc stores or zinc/sulfate sites in proteins, such as in MTs. Transient zinc increases may arise from various mechanisms, including efflux from vesicles known as zincosomes, 30 or changes in cellular redox potential facilitated by cytosolic proteins. 31 It is important to know that, in most cases, zinc signaling arises from the disturbance of intracellular zinc homeostasis, transiently and rapidly. The functioning of zinc ion transporters and MTs in the cell plays a role in maintaining cytoplasmic zinc homeostasis, which is referred to as “buffering” and “muffling”, two essential parameters that determine the availability and signaling processes of zinc. 32 Specifically, “buffering” involves zinc binding by proteins like MT, which helps maintain zinc concentration at the pM range in the cytosol. 33 The biology of MTs is characterized by zinc binding, movement within the cell, and transportation of zinc to various cellular compartments, including extracellular, endosomal, nuclear, and mitochondria. 34 The chelating agent will accelerate this process, but if gene expression such as MT is involved, “buffering” would be slow. 35 “Muffling”, on the other hand, is responsible for modulating transient changes in zinc concentrations under unsteady state conditions of cells, eventually restoring the cytosolic concentrations to their resting levels. 12 , 36 In the “muffling” process, zinc transporters regulate cellular zinc by importing, distributing, exporting, and providing zinc for zinc-dependent proteins. 36 For example, ZnT5,6 loads zinc for the enzymes of the secretory pathway, 37 , 38 while ZnT2,3,8 provides zinc for the exocytotic vesicles. 39 , 40 , 41 Moreover, MT is also responsible for zinc muffling by moving and sequestering zinc to cellular compartments, thus controlling kinetically ion concentrations. 42

In terms of time series, intracellular zinc serves as a second messenger, and its concentration transients are divided into two main types: early (fast) zinc signaling (EZS) and late zinc signaling (LZS) 43 (Fig. 1 ). The study further confirmed that EZS is transcription-independent, occurring over a timescale ranging from seconds to minutes, known as the “zinc wave”. 36 This phenomenon was first observed in mast cells and results from Fcε epsilon receptor I (FcεRI) stimulation, causing a transient, transcription-independent increase in intracellular zinc. 44 The “zinc wave” originates in the perinuclear region, including the ER, and depends on calcium influx and MEK activation. However, the precise mechanism of the “zinc wave” in cells remains poorly understood. In contrast, LZS requires the transcription of zinc transport proteins and has longer-lasting effects lasting for hours. In this case, diverse extracellular stimuli, including cytokines and growth factors, indulge the transcriptional modulation of zinc-associated proteins like ZIPs and ZnTs. Consequently, intracellular zinc homeostasis alterations regulate downstream molecular objectives, in addition to protein kinase C (PKC), ERK1/2 activation leading to neuronal cell death, cAMP-dependent protein kinase (PKA), Ca/calmodulin-dependent protein kinase II (CaMKII), phosphodiesterases (PDEs), protein tyrosine phosphatases (PTPs), and transcription factors, such as NF-κB.

Zinc signaling in the intracellular and extracellular regions. Zinc extracellular signaling is mainly involved in the physiological functions of neurosynapses and germ cells. In contrast, intracellular zinc signaling is primarily divided into two parts, EZS and LZS, which exert biological functions by activating downstream pathways, such as inflammatory signaling. Interestingly, the endoplasmic reticulum releases zinc to generate a specific zinc wave, observed within several minutes after FcεRI stimulation in mast cells. EZS early zinc signaling, LZS late zinc signaling. Green dots represent zinc

Notably, the elevated intracellular zinc has a bidirectional effect. On the one hand, zinc participates in various cellular signaling pathways, contributing to processes such as cell proliferation and differentiation. 45 , 46 , 47 , 48 For example, zinc promotes embryonic central nervous system (CNS) development by affecting STAT1 and STAT3 signaling pathways. 49 Interestingly, it has been shown that zinc has a more significant role in hematopoiesis than iron, at least in early hematopoietic stem cells. 50 In immune function-related signaling, zinc enhances the development of regulatory T cells, as induced by the transcription factor Foxp3. 51 , 52 On the other hand, excessive intracellular zinc accumulation can lead to apoptosis. Mitochondrial-derived zinc accumulation can impair mitochondrial structure and function, negatively impacting animal development and longevity in Caenorhabditis elegans . 53 Studies have also demonstrated that intracellular zinc release might occur as a response to oxidative or nitrosative stress, which could lead to the release of zinc from MT, a zinc buffer protein, thereby promoting apoptotic processes. 54 , 55 Furthermore, In a specific cell death pathway, the release of zinc and calcium within neurons leads to the subsequent phosphorylation of the potassium channel Kv2.1. 56 , 57 In conclusion, despite low intracellular free zinc concentrations, intracellular zinc signaling plays a broad and vital role in physiological functions.

Extracellular zinc signaling

Extracellular zinc is a significant signaling mediator in endocrine, paracrine, and autocrine systems. 58 , 59 It serves as a ligand for various receptor channels on the plasma membrane, including the zinc sensing receptor (ZnR/GPR39) that regulates neuronal excitation, 60 N-methyl-D-aspartate (NMDA) receptors, 61 α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, 62 voltage-dependent calcium channels (VDCC), 63 and γ-aminobutyric acid A (GABAA) receptors. 64 , 65 The progress within cell biology and chemistry has emphasized the presence and function of free or labile zinc in cellular responses, especially its neurotransmitter role in synaptic vesicles. 29 , 66 , 67 Fluctuations within brain zinc concentrations, corresponding to physiological experiences and long-term memories, indicate that free zinc is strongly associated with neurotransmitter performance. 68 Moreover, zinc released from the synapse directly activates a G-protein coupled receptor (mZnR/GPR39), sensing changes in extracellular zinc concentration and consequently regulating neuronal excitation. 69

In addition, fertilized mammalian embryos release zinc sparks. 8 , 11 The exocytotically released zinc ions coordinate with cellular calcium transients, modifying the structure of the zona pellucida to prevent polyspermy (Fig. 1 ).

Zinc signaling and tumorigenesis

Under normal circumstances, zinc concentration meets the demands of bioenergetic, synthetic, and catabolic, essential for manifesting the cells’ current activities, e.g., function, growth, and proliferation. Several mechanisms explain the antitumor function of zinc, encompassing DNA damage, DNA repair, immune function, oxidative stress, and inflammation. 70 , 71 , 72 As cell activity changes, its metabolism must be adjusted to accommodate any newly established biological energy/synthetic/catabolic requirements. Changes in zinc concentrations beyond the cell’s ability to coordinate can lead to tumorigenesis, as zinc provides the bioenergetic/ synthetic requirements of malignancy, such as the aberrant expression of zinc transporters and dysregulation of MTs binding proteins. 73 , 74 , 75

Indeed, zinc activation of two mitogen-activated protein kinase (MAPK) pathways linked to tumorigenesis, namely extracellular signal-related kinase (ERK) and c-Jun N-terminal kinase (JNK), 44 plays a significant role. These MAPKs, including ERK and JNK, are serine/threonine protein kinases that regulate cell proliferation, differentiation, and apoptosis in tumorigenesis. 76 Regarding the late zinc signaling, STAT3 stimulates the transcriptional activity of ZIP6 in zebrafish. 70 As a result, STAT3-dependent ZIP6 expression leads to downstream activation of the transcriptional repressor Snail, which contributes to the epithelial-mesenchymal transition (EMT) during embryonic development and is associated with tumor metastasis mechanisms (Fig. 1 ). Similarly, ZIP4 induces EMT-promoting migration and invasion through the PI3K/Akt signaling pathway in nasopharyngeal carcinoma (NPC). 77 Additionally, elevated expression of ZIP13 activates the Src/FAK pathway, leading to increased expression of pro-tumor metastatic genes but decreased expression of tumor suppressor genes in ovarian cancer. 73 Overall, cancer cells appear to require stimulation of oncogenic pathways by zinc to maintain their aggressiveness.

Obviously, cellular zinc signaling benefits from the storage and release of organelles and subcellular structures, which are precisely regulated by the zinc transporters and MTs. Thus, maintaining zinc homeostasis requires a complex intracellular collaboration of these functional proteins. Hypothetically, would normal cells transform into cancer if zinc homeostasis were disrupted? A plethora of studies have substantiated that dysregulation of zinc transporter proteins not only affects cell proliferation and apoptosis but also induces alterations in various signaling pathways, thus promoting cancer progression. 73 , 74 , 75 Remarkably, the lysosomal cation channel MCOLN1 has been identified as a crucial mediator of zinc influx into the cytoplasm, thereby finely controlling oncogenic autophagy in cancerous cells. 78 Additionally, alterations in zinc homeostasis have been shown to modulate the tumor immune microenvironment, exerting a significant influence on cancer progression. 79 Furthermore, the involvement of zinc in heavy metal detoxification implies that its disruption could adversely affect detoxification pathways, thereby leading to cellular stress and subsequent cancer development. 26 In conclusion, the intricate link between zinc homeostasis and cancer is an emergent field that warrants further exploration to fully elucidate the underlying mechanisms that govern the transition from disrupted zinc homeostasis to tumorigenesis.

Regulation of cellular zinc metabolism

The basic knowledge of zinc transporters.

The SLC39 family comprises four distinct groups based on amino acid sequence similarities: subfamily I (ZIP9); subfamily II (ZIP1, 2, and 3); the LIV-1 subfamily (ZIP4, 5, 6, 7, 8, 10, 12, 13, and 14); and the gufA subfamily containing ZIP11. 80 All ZIP proteins have eight transmembrane (TM) domains with conserved histidine residues within TM 4 and 5, believed to be involved in zinc transportation. The C-terminal and N-terminal ends of ZIP are located either on the cell surface or within the lumen of the organelle. 81 , 82 Members of the LIV-I family, with the exception of ZIP13, are anticipated to possess one significant, extracellular N-terminal domain, suggested to function as extracellular zinc sensors. Recently, research has provided insights into the detailed structure of ZIP transporters, including a high-resolution 3.05 Å cryo-electron microscopy structure of a ZIP-family transporter from Bordetella bronchiseptica acquired in an inward-facing, inhibited conformation. 83 Each protomer of this homodimeric transporter comprises nine transmembrane helices and three metal ions. In this architecture, two metal ions create a binuclear pore structure, and the third ion is located at an egress site facing the cytoplasm. Notably, this egress site is covered by a loop, with two histidine residues on this loop interacting with the egress-site ion, crucially regulating its release. Understanding the structure and function of ZIP transporters may offer valuable insights for developing new therapeutic strategies targeting zinc transporters to treat various human diseases.

The ZIPs are typically synthesized on ribosomes attached to the endoplasmic reticulum (ER) and later transported to various intracellular compartments. 84 Similar to other protein expressions, unstable ZIP mutant proteins are often identified in the ER. Subsequently, they undergo retro translocation and degradation by cytosolic proteasomes in a ubiquitin-independent manner, as seen in the case of ZIP13 mutant. 85 Apart from the intracellular localization of certain ZIP members, the majority of ZIP transporters are positioned on the plasma membrane, facilitating metal ion uptake into cells. ZIP7 is situated in the Golgi apparatus and ER, while ZIP13, evolutionarily closest to ZIP7, is localized in the Golgi apparatus and cytoplasmic vesicles. 85 , 86 ZIP13 is responsible for mobilizing zinc from the lumen of these compartments and plays crucial roles in cellular signaling, including the BMP/TGF-β signaling pathway, by regulating the nuclear translocation of Smad proteins and maintaining ER homeostasis.

The expression levels of numerous ZIPs, such as ZIP1, 3, 4, 8, and 12, at the cell surface, are modulated by the available concentrations of zinc. 80 ZIP10 serves as a cell surface zinc importer. 87 The transcription of ZIP10 is upregulated in zinc-depleted cells 88 and downregulated in zinc-excess conditions. The regulation of zinc transcription is mediated by pausing Pol II transcription through the action of metal response element-binding transcription factor-1 (MTF-1). Furthermore, the positioning of certain ZIP proteins varies with zinc supply and specific physiological states. During adequate zinc intake, Zip5 aligns at the basolateral plasma membrane in polarized cells. 89 In a parallel manner, ZIP14 moves to the mouse hepatocyte’s sinusoidal membrane during sharp inflammatory events. 90 As a result, this boosts zinc absorption as part of the immediate response to inflammation.

While ZIP members are known for their primary role in transporting zinc, they can also mobilize other metals such as manganese and cadmium. 91 , 92 , 93 , 94 Biochemical studies have shown that ZIP8, in particular, can transport cadmium and manganese. 95 , 96 , 97 The expression of ZIP8 mRNA is upregulated by cadmium in an NF-κB-dependent manner, contributing to the risk of cadmium-mediated lung toxicity exposed to cigarette smoke. 98 ZIP14 is evolutionarily closely related to ZIP8. 99 Similar to ZIP8, ZIP14 has the ability to mobilize various divalent cations, including cadmium and manganese. 100 Moreover, ZIP14 and ZIP8 are capable of transporting iron. 101 , 102 ZIP14 plays a crucial role as an iron transporter in vivo, especially under iron overload conditions. 103 ZIP14’s capability to transport non-transferrin-bound iron (NTBI) is considered a vital contribution to iron homeostasis. 100 Interestingly, ZIP14 possesses two spliced variants: ZIP14A and ZIP14B. These variants are present on the plasma membrane and are involved in zinc uptake. In polarized cells, ZIP14A and ZIP14B are exclusively located on the apical surface. 99

The ZnT family belongs to the cation diffusion facilitator (CDF) family of proteins. Most ZnTs are located within organellar membranes, serving various functions, such as filling vesicular zinc stores, supplying organelles with zinc, and loading exocytotic vesicles with zinc for essential biological processes. The structure of ZnT proteins is inferred from the Escherichia coli homologs of YiiP, 104 which have six TM helices (TM helices I-VI) and their N- and C-termini situated on the cytoplasmic side. 104 , 105 ZnT5, on the other hand, possesses an unusually long N-terminal region with nine putative TM domains. 106 ZnT transporters are also expected to contain a conserved zinc-binding site on TM helices II and V, with critical residues determining their metal specificity. 14 , 105 Remarkably, ZnT10 demonstrates the molecular features of a manganese transporter, likely attributed to its possession of an Asn residue rather than His in the TM helix II. 104 Furthermore, the length and amino acid sequence of the initial TM structural domain of ZnT proteins, known for containing subcellular targeting signals, display substantial variations among different ZnT proteins. Based on their protein sequence similarities, the ZnT family members can be categorized into four groups: (1) ZnT6 and ZnT9, (2) ZnT1 and ZnT10, (3) ZnT2-4 and ZnT8, and (4) ZnT5 and ZnT7. Intriguingly, members belonging to the same subfamily exhibit similar cellular locations and functional characteristics 1 (Fig. 2 ).

The protein structure and gene family evolution of zinc transporters. a Cartoon of predicted structures of ZnT and ZIP transporter proteins. The picture on the left shows an atomic model of ZnT, which is the helical reconstruction of YiiP based on X-ray structure (PDB ID code: 7y5g). In detail, the schematic topology of ZnT transporters is proposed based on the three-dimensional structure of Escherichia coli homolog YiiP. ZnTs most likely have six TM domains divided into two bundles. Specifically, one of the ZnT’s bundles contains four TM domains (MI, MII, MIV, and MV), and the other one comprises two TM domains (MIII and MVI). Each of the former bundle’s domains can independently bind zinc, tetrahedrally coordinated by two D (aspartate) and two H (histidine) in the mammalian homologs. Similarly, the figure on the right presents putative TM domains of the ZIP family (PDB ID code: 7z6m). Moreover, the topology structure of ZIP is displayed, composed of 8 TM domains with a large N-terminal domain and a small C-terminal. The spatial distribution shows that it consists of three parts, the left and right parts each contain three TM domains (red), and in the middle are two TM domains (blue). Zinc could bind to the active site of TM domain IV and V, containing conserved HND (histidine, asparagine, aspartate) and HEH (two histidines and one glutamic acid) motifs, respectively. b Gene family evolutionary tree and isoform of the ZnTs and ZIPs. The lengths of the different isoforms are labeled in the front of the isoforms, and the color lines indicate the functional domain locations of each isoform. ZnTs belong to the Zn-cation diffusion facilitator (CDF) family, responsible for transporting zinc from intracellular to extracellular. ZIPs are divided into four subfamilies, namely ZIP subfamily I (ZIP9), GufA subfamily (ZIP11), ZIP subfamily II (ZIP1-3), and LIV-1 subfamily (ZIP4-8, ZIP10, ZIP12-14)

Functionally, in the SLC30 family, ZnT1 functions primarily as a zinc exporter on the cell membrane, transporting cytoplasmic zinc ions across the membrane to the extracellular space, while other ZnT proteins are situated on the membranes of intracellular organelles. 107 Besides, ZIP10 and ZnT1 are involved in renal zinc reabsorption. 108 , 109 Members of the subfamily II of the SLC30 proteins (ZnT2, ZnT3, ZnT4, and ZnT8) play a major role in secretory tissues, with ZnT3 involved in neurotransmission, ZnT8 in insulin storage, ZnT4 in prostate secretion, and ZnT2 in lactation. 40 , 108 , 110 , 111 Besides, Additionally, TMEM163 is a recently discovered zinc transporter with a predicted transmembrane domain structure and function similar to the CDF protein superfamily. 112 Some posit that TMEM163 could be a novel member of the mammalian ZnT transporter proteins. 113 Recent discoveries indicate its significant role in maintaining zinc balance in both nerves and blood. 114 , 115 , 116

The basic knowledge of MTs

Mammalian MTs are a superfamily of nonenzymatic polypeptides that typically consist of 61–68 amino acids. 25 They are characterized by a high cysteine content, accounting for approximately 30% of their amino acids, while aromatic amino acids are absent, and histidine residues are sparsely present. However, they contain abundant thiol groups that enable them to bind to heavy metals. MTs, with their abundant thiol groups, have the capacity to bind up to 7 zinc atoms: 3 zinc atoms in the β domain and 4 zinc atoms in the α domain. 117 , 118 This unique capability enables MTs to function as a cellular zinc reserve. It is crucial to highlight that while MTs can bind other essential metals such as copper and nonessential metals like cadmium, the predominant form in human tissue is zinc-bound MT.

Human MTs can be classified into four classes, namely MT1 to MT4, comprising a total of eleven functional isoforms, with eight of them belonging to class 1. 3 MT1 and MT2 are the predominant isoforms distributed throughout the human body and expressed in various organs. Conversely, MT3 is predominantly present in the CNS, while MT4 is primarily found in the skin and other stratified epithelium, representing the minor isoforms. 119 All isoforms have an approximate molecular weight of 7 kDa and lack aromatic amino acids. Moreover, they consist of twenty cysteine residues, endowing MTs with distinctive characteristics due to the properties of thiol groups. 120 Additionally, the transcription of MT1/2 genes is governed by MTF-1, a zinc finger transcription factor that regulates the expression of metal-responsive genes. Zinc is notably the sole known metal to activate MTF-1; however, studies propose that oxidative stress might also contribute to MTF-1 activation. 121 MTF-1 is involved in regulating the zinc-responsive transcription of ZnT1 and ZnT2 and inhibiting the expression of ZIP10, 87 , 122 , 123 emphasizing its vital role in zinc homeostasis.

In humans, MTs are structurally encoded by a family of genes located on chromosome 16q13, comprising at least 11 functional members: the MT1 genes consist of 18 isoforms, including 10 functional genes ( MT1A, MT1B, MT1E, MT1F, MT1G, MT1H, MT1M, and MT1X ) and 8 pseudogenes ( MT1CP, MT1DP, MT1JP, MT1L, MT1LP, MT1XP1, MT1P3, and MT1P1 ), in addition to MT2 (also known as MT2A), MT3 , and MT4 55 , 119 (Fig. 3 ). Remarkably, as the zinc store, MT can act as both zinc receptor and zinc donor, like two sides of the same coin. 118 , 124

The protein structure and gene family evolution of MTs. a Diagram of the predicted structure of the MT2 protein, which is modeled from the reconstructed X-ray structure (PDB ID code: 4mt2). The crystallographic structure of rat liver metallothionein has been accurately determined at a resolution of 2.0 Å, achieving a low R-value of 0.176 for all observed data. b Schematic representation of zinc binding in MTs. MTs contain abundant thiol groups capable of binding with heavy metals. Due to the high thiol content, MTs can bind up to 7 zinc atoms, with 3 zinc atoms located in the β domain and 4 zinc atoms in the α domain. c Gene family evolutionary tree and isoforms of MTs are depicted in Figure X. The isoform lengths are labeled in front of each isoform, and color lines indicate the position of the functional domain of each isoform. MTs are categorized into four subfamilies: MT1 (including MT1A , MT1B , MT1E , MT1F , MT1G , MT1H , MT1M , and MT1X ), MT2 (including MT2A ), MT3, and MT4. While MT1 and MT2 are universally expressed, MT3 is primarily expressed in the central nervous system, and MT4 is predominantly expressed in the skin and other stratified epithelium tissues

Role of cellular zinc metabolism under physiological conditions

The physiological role of zinc transporters, supporting immune function.

T cells are a critical component of the immune system. 125 Among the 14 ZIP family members, ZIP6, 8, and 13 are highly expressed in human CD4 + T cells, with ZIP6 predominantly localized to lipid rafts involved in the immune synapse (IS) formation following T cell receptor (TCR) stimulation. 126 Notably, the tyrosine phosphorylation of ZIP6 was observed to increase after five minutes of TCR stimulation due to its interaction with Zap70, a crucial kinase involved in early TCR signaling. In addition, the transcriptional activity of ZIP6 leads to zinc influx, promoting the expression of MTs, which plays a crucial role in supporting T cell proliferation and is essential for T cell survival and expansion in the elderly. 127 , 128 ZIP8 and ZIP13 are primarily expressed on the lysosome and ER/Golgi membrane of T cells, respectively. 86 , 129 During T cell activation, ZIP8 facilitates zinc transport from the lysosome to the cytoplasm, resulting in increased production of IFN-γ. Notably, ZIP8 expression can be induced in response to lipopolysaccharide (LPS) stimulation, 130 , 131 leading to enhanced IL-1β production downstream of the mTORC1S6K pathway. 132 Moreover, ZIP8 is a downstream target gene of NF-κB, which negatively regulates pro-inflammatory responses through zinc-mediated downregulation of Iκκ activity. 130 Comparatively, the deficiency of ZIP8 has a substantial impact on zinc influx in effector T cells and results in reduced TCR-mediated signaling, including NF-κB and MAPK signaling, which are involved in the differentiation of T helper (Th)17 cells. 133 Similarly, mice lacking ZIP3 exhibit decreased CD4 + CD8 + double-positive (DP) thymocytes but increased CD4 + and CD8 + single-positive thymocytes, indicating its role in regulating T cell development. 134 These findings open up new possibilities for immunotherapy to improve the prognosis by modulating the zinc transporter family genes on tumors or immune cells.

Undoubtedly, the adaptive branch of the immune system relies on both B cells and T cells. 135 ZIP9 and ZIP10 play essential roles in B cell receptor signaling pathways, influencing B cell activation 136 , 137 (Fig. 4 ). The release of zinc in B cells originates from the Golgi apparatus, with ZIP9 playing a crucial role as the zinc transport participant. 136 ZIP10, on the other hand, plays different roles in the early and late stages of B cell development, regulating distinct signaling cascades. The expression of ZIP10 is mechanistically regulated in a STAT3/STAT5-dependent manner, promoting early B cell survival by inhibiting caspase activation. 137 Additionally, ZIP10 deficiency in mature B cells has been shown to attenuate both T cell-dependent and -independent immune responses in vivo. 138 ZIP10 functions as a positive regulator of CD45R in B cell antigen receptor signaling transduction, playing a crucial role in setting a threshold for human immune responses. In hepatocellular carcinoma (HCC) cell lines, ZIP10 expression was found to be positively correlated with tumor-infiltrating lymphocytes and certain immune checkpoints, including CTLA4, TIM3, and TGFB1. 139 Moreover, ZIP10 is essential for zinc homeostasis within macrophages, where zinc is involved in antimicrobial responses. 140 activated macrophages, while crucial for immune responses, can also release large quantities of inflammatory cytokines, which may have the potential to harm the host. 141 ZIP10 was identified as a significant zinc importer in macrophages that activates macrophages and promotes cytokine expression. 142 Zinc deficiency (ZD) caused by knocking down ZIP10 leads to cytoplasmic p53 accumulation and nuclear translocation of AIF, ultimately triggering apoptosis. 142 Thus, targeting ZIP10 could be a promising approach to protect the liver from inflammation damage.

The main physiological functions of zinc transporters. The zinc transporter functions are basically classified into six parts: immunity, reproduction, muscle, intestinal function, glycolipid metabolism, and neuron function. Further, the function represented by each sector is mainly divided into three parts. Each part corresponds to specific zinc transporters. The outermost circle represents diseases and cancers caused by malfunctioning zinc transporters. SCD-EDS spondylocheirodysplastic ehlers-danlos syndrome, AE acrodermatitis enteropathica, IBD inflammatory bowel disease

Notably, sepsis is an acute systemic infection triggered by the invasion of pathogenic bacteria into the blood circulation and the production of toxins. 143 Circulating zinc levels lower than expected have been linked to high mortality in sepsis patients, with MT and ZIP8 identified as two of the most highly upregulated genes in non-survivors. 144 ZIP8, in particular, has been found to be the most significantly upregulated transporter in response to cytokines, bacteria, and sepsis, indicating its unique role in innate immune function. 130 , 145 , 146 As the closest homolog of ZIP8, ZIP14 also participates in response to sepsis and is implicated in the beneficial anti-inflammatory effects of supplemental dietary zinc during sepsis, indicating its potential as a therapeutic target. 147 Additionally, the existence of “zinc waves” in mast cells provides further evidence of the involvement of zinc transporters in immune functions. 44 The release of zinc from the ER is likely mediated by ZIP7, as ZIP7 predominantly resides in the ER, and silencing ZIP using siRNA prevented the occurrence of the zinc wave. 148 , 149 Besides, ZnT1/L-type voltage-gated calcium channels (LTCCs) also contribute to the zinc wave, which interacts with ZnT1 and modulates the zinc influx from extracellular space into the cytoplasm. 150 , 151 , 152

Assistance of reproduction

During meiotic maturation, total intracellular zinc increased by ~50%. After fertilization, zinc-rich oocytes induced zinc sparks, which decreased zinc concentration by approximately 20%. The role of zinc sparks requires further investigation, but some evidence suggests that these changes in zinc levels are crucial for subsequent developmental steps and may play a role in zinc-dependent processes regulating oocyte exit from meiosis I. 11 , 153 The ZIP transporter family is believed to regulate zinc influx, and ZIP6 and ZIP10, which share 43.5% sequence identity and are on the same clade of the ZIP family phylogenetic tree, 154 are highly expressed in the oocyte during the window of meiotic maturation 155 (Fig. 4 ). The ZIP6/ZIP10 heteromer is also critical for triggering zinc-mediated mitosis, 156 forming a zinc-dependent mitotic complex consisting of ZIP6, ZIP10, pS 727 STAT3, and pS 38 Stathmin, which play roles in proven mitotic pathways. As an illustration, they are involved in processes like stathmin- reliant microtubule reorganization or HistoneH3-mediated chromatin condensation. In order to stabilize pS 38 Stathmin throughout mitosis, STAT3 serves as an effector of ZIP6/ZIP10 heteromer regulating the expression of both genes. 137 , 157 Zinc levels are often higher in cancer tissues than normal tissues, possibly due to the increased demand for tumor growth. 158 In addition to using zinc chelators to inhibit the proliferative growth of cancer tissues, 78 , 159 , 160 , 161 another potential approach is to use ZIP6 or ZIP10-blocking antibodies to hinder mitosis in cancer progression.

Maintenance of muscle function

Research indicates that approximately 90% of zinc in the body is found in tissues with slow zinc metabolism, such as skeletal muscle and bone. 162 Zinc plays a vital role in stabilizing insulin, resulting in a synergistic effect on insulin stimulation of muscle cells. 163 , 164 On the other hand, nutritional ZD can hinder skeletal muscle growth, repair, and myoblast differentiation. 165 , 166 , 167 ZIP7, known as the zinc “gatekeeper”, is localized on the ER and Golgi membrane. It has been extensively studied for its role in skeletal muscle differentiation and the regulation of glucose metabolism 168 (Fig. 4 ). The localization of zinc in myoblasts and differentiated myotubes was found to correlate with the changing localization of ZIP7. 169 Silencing ZIP7 significantly reduces intracellular zinc levels and inhibits Akt phosphorylation, resulting in a decreased number of differentiated cells, even in the presence of extracellular zinc. 170

Similarly, in myoblasts, knocking down ZIP8 also hampers myotube formation by causing a significant reduction in cellular manganese, iron, zinc, and calcium levels, leading to decreased differentiation and proliferation of myoblasts 171 (Fig. 4 ). In comparison, ZIP13 plays crucial roles in the development of bone, tooth, and connective tissue. Mutations in ZIP13 have been linked to the spondylocheiro dysplastic form of Ehlers-Danlos syndrome (SCD-EDS), 172 , 173 characterized by abnormalities in hard and connective tissues. ZIP13 knockout mice exhibit delayed growth and skeletal and connective tissue abnormalities, mirroring the phenotypes observed in SCD-EDS patients. 173

Furthermore, zinc transporters play a direct role in regulating calcium channels, modulating calcium signaling, and subsequently influencing muscle contraction (Fig. 4 ). For instance, the interaction of ZnT1 with LTCCs enables zinc entry from the extracellular space into the cell membrane, thereby contributing to calcium signaling involved in excitation-contraction coupling in skeletal muscle. Additionally, ZnT1 directly inhibits the activity of L-type calcium channels by binding directly to the β-subunit, Ca v β. 151 ZIP7 and ZnT7 are involved in regulating the release of zinc into the sarcoplasmic reticulum (SR) in skeletal muscle. Intracellular zinc can then modulate ryanodine receptor (RyR)-mediated calcium release from the SR. Notably, the cytoplasmic C-terminal tail of ZnT1 alone can inhibit the channel, suggesting that the inhibition of L-type calcium channels by ZnT1 is independent of zinc channel function. 174

Regulating gastrointestinal (GI) function

The dietary complex releases zinc, which is primarily absorbed by enterocytes in the upper part of the small intestine. The luminal surface cells of the intestinal epithelium originate from intestinal stem cells (iSCs) and comprise various cell types, including enterocytes, goblet cells, enteroendocrine cells, tuft cells, and Paneth cells. These cells express members of both the ZIP and ZnT families involved in zinc transport. 175 ZIP4 is particularly important for zinc uptake and is closely related to the process. Loss of ZIP4 during embryonic development leads to lethality 176 (Fig. 4 ). Previous research has established that ZIP4 is predominantly localized to the apical brush border of enterocytes, facilitating zinc uptake from the intestinal lumen. Furthermore, the expression of ZIP4 is regulated through proteolytic processes that respond to changes in the zinc concentration within enterocytes. 177 , 178 Mutations in ZIP4 can lead to acrodermatitis enteropathica, a rare autosomal recessive metabolic disorder characterized by ZD, commonly observed in infants. 179 , 180 In the case of ZD, ZIP4 is translocated to the apical surface of the small intestinal epithelial cells. However, when zinc levels are adequate, the mRNA of ZIP4 becomes unstable, and the protein is internalized and quickly degraded. 181 Intestinal ZnT1 plays a crucial role in zinc acquisition and processing. It is highly expressed in the epithelium of the esophagus, duodenum of the small intestine, and cecum of the large intestine, suggesting its involvement in zinc efflux and absorption into the systemic circulation. 182 Remarkably, the expression of ZnT1 is influenced by dietary zinc supplementation. Upon zinc supplementation, there is an increase in ZnT1 mRNA expression. 183 As a result, both ZIP4 and ZnT1 play vital roles in regulating zinc intake.

Zinc plays a vital role in maintaining the homeostasis of intestinal epithelial cells, and its deficiency can lead to alterations in their integrity and function. 184 Zinc transporters play a significant role in regulating cellular function to support intestinal epithelial homeostasis. Among them, ZnT2 has been proven to be mainly expressed in Paneth cells, which are located within Lieberkühn crypts. 185 In these specialized secretory cells, ZnT2-mediated zinc absorption into intracellular vesicles is crucial for controlling cytoplasmic zinc levels and cellular function. 185 , 186 ZIP4, as mentioned earlier, is important for zinc uptake in the intestine and is essential for the differentiation and maintenance of Paneth cells. 176 Additionally, ZIP4 also contributes to the proliferation of intestinal epithelial cells. 176 Mice lacking ZIP4 exhibit disrupted villus integrity, highlighting the significance of ZIP4 in preserving the architecture of the intestinal epithelium. ZIP7, localized to the ER, is also highly expressed in the intestinal crypts. 108 , 187 Furthermore, the deletion of ZIP7 greatly enhances the ER stress response of proliferating progenitor cells, leading to apoptosis and disrupting intestinal epithelial cell proliferation and dryness. Indeed, the findings indicate that ZIP7 plays a vital role in promoting both the proliferation and maintenance of stemness in intestinal epithelial cells. 187

Recent studies have suggested that zinc plays a crucial role in preserving the integrity of mucosal barriers, which is linked to the immunological responses of gastrointestinal diseases in the mucosa 188 , 189 , 190 (Fig. 4 ). ZIP14, found at the basolateral membrane of enterocytes along the villus, is particularly abundant in the proximal region of the small intestine. 191 Deletion of ZIP14 in the intestine has been shown to result in compromised barrier function. 101 The reason is that ZIP14 maintains the intestinal barrier by stabilizing occludin’s phosphorylation, known as a tight junction protein. Studies have revealed that mice lacking ZIP14 display a disruption in the tight junction complex and increased permeability, potentially due to impaired zinc-dependent activation of ZnR/GPR39. The absence of ZIP14 in mice results in reduced zinc transport into enterocytes, which in turn results in a range of pathologies. These include reduced intestinal barrier function, adiposity, muscle wasting, impaired glucose processing, and skeletal defects that manifest with aging. 191 , 192 , 193

In the small intestine, ZnT2 assumes a vital function in cytoplasmic zinc buffering, which is essential to Toll-like receptor 4 (TLR4) expression, initiation of pathogen-activated NF-κβ translocation, in addition to the release of cytokine in response to infectious challenges. 185 , 194 Furthermore, ZnT2 is indispensable for the development of lysosome biogenesis and bacterial-stimulated autophagy, 195 facilitating a powerful host defense and resolution machinery against enteric pathogens. In conclusion, this evidence suggests ZnT2 serves as an innovative modulator for mucosal inflammation in colonic cells and plays a crucial role in coping with infectious colitis, opening up possibilities on manipulating ZnT2 as a novel treatment strategy to particular intestinal infections. 194 ZIP8 is crucial for T cell activation, and recent studies have highlighted its significance in T cell function and innate immunity, which may have important implications in the context of inflammatory bowel disease (IBD). 145 , 196 In a study by Li et al., a novel association between Crohn’s disease (CD) and ZIP8 was identified. 197 Healthy carriers of the ZIP8 variant exhibited changes in intestinal microbiota that partially overlapped with those observed in CD patients. This suggests that disturbances in zinc homeostasis could be linked to ecological imbalances in the gut, potentially contributing to the pathophysiology of CD.

Maintaining neuron functions

As a neuromodulator, zinc is crucial in managing diverse synaptic transmissions, such as glutamatergic, GABAergic, and glycinergic. 61 , 198 , 199 In addition, it modulates both short-term and long-term synaptic plasticity, enhances auditory processing, and refines sensory stimulus discrimination. 200 , 201 , 202 , 203 , 204 Following physiological activity, vesicular zinc is released and modulates neurotransmission by interfacing with postsynaptic neurotransmitter receptors and activating mZnR/GPR39 signaling. 199 , 205

So far, the specific functions of zinc transporters have been described in the brain (Fig. 4 ). ZnT3, a membrane zinc transporter responsible for concentrating zinc into neuronal presynaptic vesicles and co-released with glutamate upon depolarization, is pivotal in maintaining neuron functions. 206 , 207 , 208 ZnT3 exhibits predominant expression in the brain, particularly in key regions such as the hippocampus, amygdala, and cerebral cortex. 206 In various brain areas, including the cerebral cortex, hippocampus, amygdala, and dorsal cochlear nucleus (DCN), the transporter is abundantly present in excitatory neurons, playing a crucial role in channeling zinc into presynaptic vesicles. 209 Upon synaptic activity, vesicular zinc is released from terminals enriched with ZnT3 and diffuses across the synaptic cleft 61 to modulate multiple postsynaptic receptors, 199 , 210 l including the zinc-sensitive N-methyl-d-aspartate receptor (NMDAR). 61 The deletion of ZnT3 leads to the suppression of Erk1/2 signaling in MF terminals, resulting in the release of MAPK phosphatase and impairing hippocampus-dependent memory processes. 211

ZnT1, another zinc transporter, has been suggested to interact with NMDA receptors at synapses. 212 ZnT1 specifically associates with the C-tail of the NMDAR GluN2A subunit. This ZnT1/GluN2A complex may be influenced by synaptic plasticity, and disruptions in ZnT1 expression led to significant changes in dendritic spine morphology. 61 The primary targets of the released zinc are NMDARs containing GluN2A, which are responsive to nanomolar levels of extracellular zinc, thereby inhibiting receptor function. 213 Moreover, ZIP12, exclusively expressed in the CNS, plays a vital role in neuronal differentiation, including tubulin polymerization and neurite extension, by facilitating zinc uptake into the cytosol. 214 , 215 Excessive expression of ZIP12 has been observed in schizophrenia. 216

Additionally, different neuronal populations within the hippocampus express the plasma membrane zinc transporters ZIP1 and ZIP3. While ZIP1 controls the influx of zinc into postsynaptic cells, ZIP3 manages the re-uptake of zinc into dentate granule cells. 217 SHANK3, a critical scaffold protein in the PSD of excitatory glutamatergic synapses, is sensitive to changes in zinc concentrations. ZIP4 is found in the postsynaptic region and interacts with HOMER1 and SHANK3. 218

Furthermore, mutations in ZIP8 have been frequently reported in relation to the development of schizophrenia. Genome-wide association studies (GWAS) have indicated that a specific variant of the zinc transporter ZIP8 is significantly linked to the risk of schizophrenia and Parkinson’s disease (PD). 219 Severe homozygous loss-of-function mutations in ZIP8 lead to a type-II congenital disorder of glycosylation, increasing the risk of schizophrenia. 93 , 220 Furthermore, ZIP8 hypofunction may contribute to psychiatric risk by causing glutamate receptor hypofunction and heightened inflammation. As a result, selectively enhancing glutamate function and targeting anti-inflammatory mechanisms could be beneficial for schizophrenia patients with ZIP8 hypofunction. 221 , 222 In conclusion, zinc transporters are essential in neuronal cells to maintain neurological function primarily by keeping intracellular zinc ion homeostasis.

Involving in glucolipid metabolism

Zinc’s role in insulin crystal formation is widely recognized, with insulin crystallizing in hexamers when two or more zinc atoms are present. 223 Notably, systemic zinc dysregulation has been demonstrated in both type 1 and type 2 diabetes 224 (Fig. 4 ). Pancreatic β-cells, in particular, have elevated zinc concentrations compared to other cell types. 105 Therefore, if pancreatic β-cells maintain adequate zinc concentrations, the activation of zinc transporters is required.

ZnT8, found in β-islet cells, stands as the most extensively studied zinc transporter involved in insulin formation and secretion. 225 , 226 , 227 Particularly, the C variant of ZnT8 at single nucleotide polymorphism (SNP) rs13266634 has shown enrichment in individuals with type 2 diabetes, implying its potential influence on diabetes risk. 228 Notably, polymorphisms in ZnT8 are associated with both type 1 and type 2 diabetes mellitus. 229 , 230 , 231 Furthermore, ZnT8 autoantibodies are detected in approximately 60–80% of new cases that are clinically confirmed as being affected by type 1 diabetes within the patient population. 232 When combined with the preexisting detection markers such as protein tyrosine phosphatase IA2, the detection of type 1 diabetes-associated autoimmune responses increases to 98% at the onset. 233 Interestingly, a distinctive connection between ZnT3 and ZnT8 gene expression in insulin-secreting INS-1E cells has been observed. Conditions that cause an up-regulation of ZnT3 expression, such as high glucose concentration or DEDTC treatment, lead to a down-regulation of ZnT8 expression. 234 Conversely, knock-down of ZnT3 results in an up-regulation of ZnT8 expression, and vice versa. 235 Additionally, β-cells express ZIP4, ZIP6, and ZIP7, which play a role in zinc uptake into β-cells, essential for proper insulin packaging, 236 , 237 , 238 which is required for the proper insulin packaging (Fig. 4 ).

Currently, the majority of studies have focused on β cells, with only a limited number of studies involving α cells. α cells are responsible for secreting the hormone glucagon, which is essential for the regulation and control of hypoglycemia in the body’s metabolic system, and zinc plays a crucial role as a signal molecule in glucagon secretion. Interestingly, overexpression of ZnT8 in α cells leads to the inhibition of glucagon secretion, which may hold potential benefits for T2D. 239 Researchers have examined the expression of zinc transporters using fluorescent measurements. 238 ZIP1 and ZIP14 were found to be the most abundant influx transporters in pancreatic α cells, while ZnT4, ZnT5, and ZnT8 were the dominant efflux transporters.

Besides, zinc has been demonstrated to exert an insulin-mimetic effect on target organs, including adipocytes. 240 Specifically, it stimulates lipogenesis in fat cells, even in the absence of insulin. Among all zinc transporter functions in lipid metabolism, the role of ZIP13 serving in adipocyte browning has attracted much attention in recent years. 241 The browning of adipocytes means converting white adipocytes that store energy into beige adipocytes, the energy-consuming brown adipocytes. Fat atrophy is reported in patients with Ehers-Danlos syndrome with mutations in ZIP13 function loss. 173 Furthermore, ZIP13 has been established as a significant regulator of beige adipocyte differentiation, and it negatively regulates C/EBP-β protein levels. This suggests the physiological importance of the ZIP13-C/EBP-β axis in beige adipocyte biogenesis and thermogenesis, and also highlights its potential in obesity treatment. 242 Above all, abnormal glucolipid metabolism is not only contributing to the process of diabetes and obesity, but also involved in carcinogenesis, 243 , 244 suggesting the unique function of zinc transporters both in clinical and preclinical investigations.

The physiological role of MTs

Involvement in cell proliferation, differentiation, and apoptosis.

Numerous studies have demonstrated that MTs regulate zinc, notably in relation to cell cycle regulation and cell proliferation. 245 MT predominantly resides in the cytoplasm. 246 Its peak concentration appears during the late G1 and G1/S cell cycle stages. 247 The nucleus uptake of MTs may be linked to safeguarding cells from DNA damage, apoptosis, and gene transcription through various cell cycle phases. 248 , 249

Additionally, MT serves as a donor of zinc to an array of metalloproteins and transcription factors. 250 DNA-binding proteins featuring zinc finger domains are pivotal in orchestrating DNA transcription processes. The central domain of p53 contains a zinc finger motif, which relies on zinc for structural stability. Apothionein, also known as zinc-free MT, has the ability to remove zinc from p53, leading to a reduction in its transcriptional activity and subsequently suppressing its DNA binding capabilities. 251 Analogous interactions are observed with the p50 subunit of NF-κB, where MT plays a role in stabilizing the p50-DNA complex. Such interplays have been widely reported for other transcription factors, including Sp1 and TFIIIA. 252 , 253 Evidence suggests that MT can modulate cellular activity through the regulation of Zinc. For instance, the protein Bmi1, a member of the Polycomb group (PcG), serves as a crucial epigenetic modulator of stem cell behavior, including aspects like differentiation and self-renewal, throughout both typical maturation and in advanced organ systems. 254 MT1 plays a facilitating role in this modulation by enhancing resistance, particularly by improving the cellular capacity to combat oxidative stress encountered in their microenvironment, within the satellite cell clusters. 255 It is worth noting that in DCs treated with zinc chloride (ZnCl 2 ), MT1 insufficiency fails to promote a regulatory phenotype specifically aimed at modulating T cell behavior or stimulate the proliferation, such as active growth, of FoxP3 + T cells. 256 , 257 Besides, MT3’s important contribution to osteoblast differentiation is by counteracting oxidative stress. 258 Its inhibition of 3T3-L1 adipocyte differentiation is an indirect function, involving the suppression of PPARγ transcriptional activity and a decrease in reactive oxygen species (ROS) levels during early adipogenesis. This indicates that MT3 could be a new target for obesity prevention and treatment.

Furthermore, MTs have also been found to be involved in apoptosis. Recent research has identified XAF1 as a suppressor of MT2A, promoting apoptosis in cellular responses to heavy metals. 259 XAF1, an exclusive transcriptional target of MTF-1 involved in apoptotic signaling, opposes the survival effects of MT2A, which is also regulated by MTF-1. 259 Therefore, the induction of XAF1 by heavy metals leads to an apoptotic shift in the stress response by destabilizing MT2A. Additionally, MT mitigates nitrosative damage and cell death caused by angiotensin II (Ang II)-induced NOX. 260 More specifically, MT2A functions as an anti-apoptotic protein by reducing the expression of caspase-3, caspase-9, caspase-12, and BAX. 261 In addition, MT2A shields against cardiac failure induced by ER stress by reducing myocardial apoptosis.

Maintaining the redox balance

Oxidative stress is defined by an imbalance between oxidants and antioxidants, which arises from the excessive generation of ROS and a decrease in the rate of their elimination by the antioxidant defense system. 262 The excessive production of ROS, including superoxide, hydrogen peroxide (H 2 O 2 ), hydroxyl radicals (·OH), and NADPH-oxidase (NOX), combined with reduced antioxidant capacity, contributes to a pathological imbalance that leads to oxidative stress and inflammation. 121 Further, this condition would cause cellular and tissue damage, eventually leading to chronic illnesses such as obesity, diabetes, and cancer. 263 , 264

Apart from intracellular antioxidants like glutathione (GSH), heme oxygenase-1 (HO-1), superoxide dismutase-1, and nicotinamide adenine dinucleotide phosphate (NAPDH), MTs also serve as a redox buffer by interacting with and scavenging reactive species. 265 , 266 Additionally, as a key source of intracellular zinc, MTs play a vital role in the catalytic activation and structural stability of metalloenzymes. 19 , 267 Notably, it aids in the structural stability of nitric oxide synthase (NOS), 268 MMP-9, 269 and superoxide dismutase (Cu/Zn SOD). 270 Moreover, MTs become particularly active when the presence of the reduced GSH form is blocked. 271 , 272 In this condition, MTs effectively neutralize free radicals using the Zn-MT redox mechanism. MTs contribute to a new pool of thiol in the cell cytosol, mitigating the detrimental effects induced by GSH depletors. 273 They scavenge ROS through thiol groups present in cysteine residues, displaying stronger antioxidative activity than the majority of well-known antioxidants. 255 , 274 Remarkably, MT2A exhibits a 100-fold greater capacity to scavenge free •OH and peroxyl radicals when compared to GSH. In response to oxidative stress, the expressions of MT2A and HO-1 are heightened due to ROS. 275 MTs also modulate the phosphorylation of ERK and regulate ROS through HO-1. 276 The potency of MT3 in eliminating ROS has been notably linked to its metal-binding affinity. 277

MTs’ expression is subject to dynamic regulation by both oxidative stress and cellular zinc levels. 270 , 278 , 279 Under oxidative stress, disulfide bonds are formed, leading to the release of bound metals, particularly zinc, from MTs. While zinc lacks inherent redox capacity, it is regarded as a powerful and crucial antioxidant agent. 279 , 280 Several studies have linked cellular zinc depletion to elevated oxidant levels and oxidation parameters. Zinc’s antioxidant properties arise from its direct and indirect interference with target structures. 281 These functions comprise the induction of MT expression and GSH synthesis, regulation of oxidant production, association with cysteines (alongside release by other oxidants), and modulation of redox signaling. Typically, MT is found in the cytoplasm, but it can also translocate into the nucleus to safeguard DNA from damage and interact with transcription factors, which will be further elaborated on later. 34

In addition, MT1 and MT2 have differential effects on ROS levels in various organs and tissues. Transcriptionally induced MT1/2 strengthens the liver’s defense system against alcoholic toxicity by reducing ROS and inflammation. 282 Moreover, IL-22Fc induces MTs in the liver, resulting in decreased hepatic ROS production, stress kinase activation, and inflammatory functions, leading to the amelioration of nonalcoholic steatohepatitis. 283 MTs play a crucial part in the antioxidative effects of D609, a compound that safeguards RPE cells from oxidative cell death induced by sodium iodate (SI). 284 Dysregulated MT expression in ascending aortic smooth muscle cells from patients with bicuspid aortic valve (BAV) might lead to an insufficient response to oxidative stress, potentially triggering aneurysm formation. 285 Recently, MT3 has shown promise for future translational medicine research in osteogenesis due to its effective ROS elimination capabilities. 258

Besides, the transcription factor MTF-1 enhances cellular protection against oxidative stress, as it responds to alterations in the cell’s redox status. 286 Specifically, MTF-1 triggers the expression of the Selenoprotein 1 ( Sepw1 ) gene, responsible for encoding an antioxidant GSH-binding protein that effectively scavenges free radicals. 45 Furthermore, MTF1 can be activated by Sirt6, providing liver protection against alcohol-related liver disease. 282

Orchestrating inflammatory reactions

Extensive research has explored the implications of MTs in inflammation. As mentioned previously, oxidative stress acts as a potent catalyst for releasing inflammatory cytokines, 287 whereas MT1/2 effectively inhibits the activation of pro-inflammatory cytokines like IL-6, IL-12, and TNF-α. 288 Studies have demonstrated that bacterial endotoxin LPS acutely induces MT1 expression in various organs, such as liver, heart, kidney, and brain tissues involved in systemic response. 289 , 290 , 291 In the cellular environment of Histoplasma capsulatum-infected macrophages, the concentrations of MT1 and MT2 expression are regulated by the activation of STAT3 and STAT5 signaling pathways, which are also involved in zinc import, thereby regulating ZIP2. 292 Liu et al.‘s research revealed that MT2 knockdown increases LPS-induced IL-6 production in endothelial cells, 293 indicating a protective role against inflammatory responses. Similarly, the absence of MT1/2 significantly exacerbates renal oxidative damage and inflammation induced by intermittent hypoxia, with the Nrf2 signaling pathway implicated. 294

NF-κB, a crucial inflammation-associated transcription factor, mediates MT1 gene expression. 295 , 296 Restoring MT1 expression in cells lacking MT results in the recovery of NF-κB p65 subunit levels, along with a subsequent increase in NF-κB activity related to cellular signaling, and improved protection against apoptosis. These findings indicate that MT1 plays a significant role as a positive regulator of NF-κB activity. 297 In contrast, MT2A regulates the cell’s inflammatory response by inhibiting NF-κB and endothelial-overexpressed LPS-associated factor-1 (EOLA1). 293 The increased MT2 expression has demonstrated the ability to reduce NF-κB activity in tumor cells, keloid fibroblasts, and cardiomyocytes. 298 , 299 , 300 Furthermore, zinc functions as a robust and selective suppressor of IFN-λ3 signaling, resulting in elevated MT levels. 301

To summarize, MTs possess a wide-ranging and complex ability to regulate inflammatory responses. They serve crucial functions in maintaining a balance by restraining the release of pro-inflammatory cytokines and managing oxidative stress. MTs also influence inflammatory reactions through their impact on essential signal transduction pathways and the expression of diverse transcription factors. The intricate interplay between MTs and crucial elements like zinc forms a complex network of protective mechanisms.

Facilitating detoxification of metals

MTs are not only involved in the regulation of zinc homeostasis but also play significant roles in heavy metal detoxification, particularly for cadmium and arsenic. 302 , 303 Cadmium, listed as one of the most hazardous substances for human health, accumulates in various organs causing severe oxidative stress and other adverse effects. The protective role of MTs against cadmium toxicity becomes particularly notable here. Exposure to cadmium can displace zinc from MTs and other proteins, leading to an elevation in cytoplasmic zinc levels. This in turn activates MTF-1, inducing MT overexpression. 304 Interestingly, the cadmium/zinc quotient in MTs determines the level of protection offered to cells against cadmium toxicity. With a lower cadmium/zinc quotient, cells are more protected, while an increased quotient reduces this protection due to the decreased availability of zinc sites for cadmium interaction. 305 The effectiveness of this protection mechanism was vividly demonstrated in a study conducted among individuals living in a cadmium-contaminated area in China. The study found that individuals with a good zinc status had a notably lower prevalence of renal tubular dysfunction when compared to those who had lower levels of serum and hair zinc. 306

Exposure to arsenic can result in toxicity, primarily caused by the generation of reactive oxygen intermediates during its redox cycling and metabolic activation. 307 Zinc acts as a vital safeguard against acute arsenic toxicity through two distinct protective mechanisms: restoration of antioxidant activity and increased expression of MTs. 303 The enhancement of metal response element (MRE) and antioxidant response element (ARE) activation, facilitated by essential nutrients like zinc, holds the potential to be beneficial in reducing arsenic toxicity. These elements are crucial as they can transcribe the expression of MTs, particularly by minimizing ROS-mediated cytotoxicity, thus adding another layer of protection against arsenic’s harmful effects. 308 Thus, the multifaceted relationship between MTs and zinc contributes to both heavy metal detoxification and zinc metabolism. Their cooperative function safeguards cellular integrity against the toxicity of heavy metals.

Cellular zinc metabolism in tumorigenesis

As previously mentioned, there exists a correlation between changes in zinc levels and cancer progression. However, it is essential to acknowledge that the nature of this correlation may vary among various kinds of cancer. Multifaceted effects of zinc in promoting or inhibiting tumor growth underscores this complexity, with distinct mechanisms operating in various cancer types. Recent evidence has been accumulating, suggesting a link between ZD and the development of cancers. Numerous processes are involved in zinc’s anti-tumor activity, encompassing DNA damage and repair, oxygenation, immunity, and the inflammatory process. 45 , 51 , 309 , 310 , 311 Yet it is important to note an increased level of zinc concentration has also allowed for an improved rate of cancer. 312 , 313 Since zinc is always characterized by playing a crucial role in growth arrest after the first meiotic division, 153 , 314 it also contributes to the proliferation of cancer cells. Furthermore, zinc regulation towards cancer heavily relies on the involvement of zinc transporters. Abnormal expression of these two families is primarily a result of gene dysregulation and translocation from organelles, which result in tumorigenesis mainly through two ways, the regulation of downstream molecular targets and the unsteady state of zinc homeostasis. 315 Based on this point, we summarized several cancer types whose development is strongly associated with zinc transporters.

Breast cancer (BC)

Studies have reported that BCs, along with malignant cell lines, exhibit a higher accumulation of zinc in contrast to normal mammary epithelium. 316 , 317 Moreover, the degree of zinc accumulation has been linked to cancer progression and malignancy. 318 , 319 ZIP6 (also known as LIV-1), was initially recognized as an estrogen-mediated gene since 1988. 134 , 320 , 321 It is observed to be upregulated in estrogen receptor-positive breast cancers and shows a positive correlation with estrogen receptor status. During gastrulation in zebrafish, zip6 is transactivated by STAT3. Elevated expression of zip6 results in nuclear retention of Snail, which is also known to be a zinc-finger transcription factor, which subsequently represses the expression of E-cadherin, resulting in cell migration 322 (Fig. 5 ). Indeed, E-cadherin performs its function as a calcium-induced TM glycoprotein, with its decreased expression linked to BC metastasis. 323 , 324 Taylor’ research observed a positive association between STAT3 and ZIP6 in breast cancer samples. 320 Furthermore, the induction of ZIP6 expression by STAT3 induces the translocation of ZIP6 to the plasma membrane and facilitates zinc influx, which is triggered by N-terminal cleavage. 157 Consequently, the zinc influx activates the zinc influx/GSK-3β inhibition/Snail activation/E-cadherin loss pathway, resulting in cell rounding and detachment (Fig. 5 ).

The molecular mechanism of zinc transporters and MTs in BC and prostate cancers. The left figure represents the mechanism of ZIP-mediated proliferation and EMT procession in BC. ZIP7 locates on the endoplasmic reticulum and is highly expressed in tamoxifen-resistant BC cells. After CK2 phosphorylation, ZIP7 was stimulated to transport zinc from intracellular stores, for example, the Golgi apparatus. Subsequently, the increasing zinc concentration can promote proliferation by activating the downstream PTPs, AKT, and ERK1/2 signaling. ZIP6 and ZIP10 locate on the cytomembrane. In addition, ZIP6 is induced by STAT3 and then translocated to the plasma membrane, promoting the accumulation of cellular zinc. The zinc influx caused by ZIP6 and ZIP6/ZIP10 heteromer triggers the AKT pathway and inhibits GSK-3β, finally boosting the EMT process by reducing the nuclear translocation of Snail. MT2A play a dual role in zinc homeostasis and BC cell proliferation. They can chelate zinc ions to reduce zinc cytotoxicity-induced apoptosis, while also releasing zinc ions to promote cancer cell proliferation through cdc25A activation. The figure on the right elucidates the mechanism of zinc transporter involved in prostate cancer. RREB-1 downregulates ZIP1 expression, leading to zinc homeostasis imbalance in prostate cells. ZIP1 downregulation reduced zinc influx, thus degrading the Bax pore expression level, which is the channel for cyto-C releasing into the cytoplasm. Consequently, the apoptosis induced by cyto-C is inhibited. Moreover, decreasing zinc concentration attenuates the inhibition of m-aconitase, which drives citrate oxidization in the TCA cycle. Meanwhile, the inhibitory effect of zinc on the NF-κB signaling pathway was diminished, as well as the inhibitory effect on the expression of HIF-1α, PSA, AP-N, and VEGF, which contributes to the invasion and proliferation. Besides, HOXB13 upregulates the expression of ZnT4 in prostate cancer through transcriptional regulation. EMT epithelial-mesenchymal transition, CK2 casein kinase 2, PTPs protein tyrosine phosphatases, RREB-1 Ras-responsive element binding protein 1, m- aconitase mitochondrial aconitase, cyro-C cytochrome C, PSA prostate-specific antigen, AP-N activity of urokinase-type plasminogen activator and aminopeptidase N, VEGF vascular endothelial growth factor, TCA tricarboxylic acid

However, despite the above discoveries, a solid link of ZIP6 to lymph node metastasis has not yet been entirely determined. There is evidence that ZIP6 is negatively correlated with EMT. 325 E-cadherin is downregulated in the condition of ZIP6 silencing. 326 In BC cells, exposure to high glucose results in a notable elevation of intracellular zinc levels, and it also leads to decreased mRNA expression of ZIP6 in the context of hypoxia. This downregulation of ZIP6 is associated with increased cell viability and reduced E-cadherin expression. 327 Hypoxia, which arises due to the aggressive proliferation of tumor cells, has previously been shown to trigger BC cells to undergo EMT, thereby promoting cell survival and malignant progression. 328 , 329 Similarly, the knockdown of ZIP6 blocks the balance of intracellular zinc levels, resulting in more tolerant cells in hypoxic environments. 321 Furthermore, some evidence suggests ZIP6 is associated with a more favorable prognosis. An illustration of this is that ZIP6 serves as a biological marker for estrogen receptor-positive luminal-type-A breast cancer, which is a molecular subtype associated with a more favorable prognosis. 330 , 331 , 332

Among the ZIP zinc transporter family, ZIP10 shows the highest similarity to ZIP6, sharing 43.5% sequence identity, which implies that they likely possess comparable roles in the regulation of cell migration. 154 , 333 As an indicator of metastasis and aggressiveness in cancer progression, ZIP10’s clinical relevance extends to its correlation of estrogen receptor ERBB3 and STAT3 among BC cases, 320 , 334 , 335 like the previously mentioned ZIP6. In mitosis, ZIP6/ZIP10 heteromer-induced zinc influx into cells leads to the formation of pS 727 STAT3 from pY 705 STAT3. PY 705 STAT3 serves as a transcriptionally promoted form of the protein, 336 , 337 impelling numerous malignant cancer features, such as EMT in HER2-positive BCs. 338 Chandler et al. discovered that the elevated presence of ZIP10 as well as the reduction in ZIP4, ZIP7, and ZIP11 were consistent mechanisms linked to zinc overaccumulation in the cells of malignant mammary glands. 39

Furthermore, the expression of ZIP7 has been demonstrated to be remarkably upregulated in BC cells. 339 , 340 ZIP7 functions as a zinc importer, moving zinc from intracellular stores (i.e., ER, Golgi) to the cytoplasm upon stimulation by the phosphorylation of CK2 168 (Fig. 5 ). The upregulated expression of ZIP7 facilitates the proliferation and aggression of tamoxifen-resistant MCF-7 cells by activating epithelial growth factor receptor (EGFR), insulin-like growth factor receptor 1 (IGF1R), and tyrosine kinase Src. 339 Activated ZIP7 is essential to the proliferation of drug-resistant estrogen receptor-positive BC. 340 Additionally, it is of great importance to note that ZIP7 plays a vital role in ferroptosis, which may establish a connection between ferroptosis susceptibility and treatment-resistant cells, as described in reference. 159 Mechanistically, ZIP7 overexpression induces zinc mobilization from the ER and Golgi, 341 triggering tyrosine kinase signaling as well as enhancing the aggressiveness of MCF7 cells 148 , 339 (Fig. 5 ). Besides, ZIP13 expression and subsequent mobilization of zinc from the ER/Golgi are essential for stimulating BMP/TGF-β signaling in connective tissue. 173 Overexpression of ZnT2 has resulted in cell cycle shifts, increased apoptosis, and decreased proliferation and invasion capabilities within MDA-MB-231 cells. 39 To summarize, being a risk factor for BC, zinc ions are regulated by ZIPs and ZnTs. Unlike ZnTs, the transporter proteins responsible for zinc inward flow, ZIPs, appear to be oncogenes in BC.

Indeed, there is evidence of mechanistic heterogeneity in the function of zinc transporters across different subtypes of BC. A notable association has been found between ZIP6 mRNA expression and improved overall survival (OS) among the whole cohort, the same as patients with luminal A and HER2-positive tumors. 342 Conversely, in luminal B and triple-negative BC (TNBC) subtypes, patients with high levels of ZIP6 expression showed worse OS. Besides, within the context of this heterogeneity, ZIP4 transporter plays a distinct role, particularly in TNBC. The upregulated ZIP4 expression results in enhanced zinc influx and promotes tumorigenicity in TNBC. 343 Interestingly, the intracellular zinc concentration in the BrM2 cell line, which metastasized to brain tissue, was found to be twice as high as that in the TNBC cell line MDA-MB231. Additionally, ZIP8, ZIP9, and ZIP13 have been demonstrated to be upregulated in BrM2 cells. The correlation between intracellular zinc concentration and BC cell metastatic potential is implied.

However, excess zinc accumulation typically triggers apoptosis, necessitating mechanisms in malignant breast cells to protect themselves from zinc-induced cell death. MTs serve as buffers for cellular zinc and shield cells from zinc toxicity. Breast tumors are known to hyper-accumulate zinc, with tissue biopsies of invasive ductal carcinoma overexpressing MTs in up to 88% of cases, 344 reflecting aberrant zinc accumulation and associated with poor prognosis. Furthermore, MT expression inversely correlates with estrogen receptor expression, indicating an important protective role for MT overexpression in highly invasive and poorly differentiated breast carcinoma. Specifically, TCGA data showed that patients with estrogen receptor α-positive BC had reduced concentrations of MT1 genes. 345 Nevertheless, it should be noted that not all malignant breast cells express MTs, implying the presence of alternative mechanisms to prevent zinc cytotoxicity. ZnT2, similar to MTs, exhibits zinc-responsive expression due to MREs in its promoter, as previously mentioned. 122 The overexpression of ZnT2 has been observed in MT-null BC cells (T47D). It is positively correlated with zinc accumulation, thereby conferring a protective effect against excess zinc-induced cytotoxicity. 346

Additionally, MT overexpression is primarily observed in the invasive ductal carcinoma subtype of BC and is associated with p53 inhibition and resistance to apoptosis. 122 , 344 As previously mentioned, apo-MT was able to eliminate zinc from p53, and reduced the subsequent transcriptional activity, yet it was incapable of binding to DNA. 251 Moreover, MTs can influence BC growth through cell cycle effects. In BC cells, suppression of MT2A results in an upregulation of ataxia telangiectasia-mutated (ATM) expression and a concurrent decrease in cell division cycle 25 A (Cdc25A) levels., 347 which is known as playing a pivotal character in facilitating the cell cycle transition from G1 to S phase. Interestingly, cdc25c, which originated from the cdc25 protein family as well, has been characterized as a zinc-binding metalloprotein. Its role involves dephosphorylating and activating the Cyclin B/cdk1 complex, which subsequently governs the initiation and advancement of mitosis. 348 On the other hand, p53 is identified as the substrate related to ATM coping with DNA damage. 349 The subsequent induction of CDK inhibitor p21 CIP1/WAF1 transcriptional activity results in a G1-growth arrest. 350 Thus, MT2A may serve as a zinc donor and plausibly promote cell cycle progression through the ATM-cdc25A-dependent pathway in BC.

To sum up, zinc metabolism is critical to the pathogenesis of BC, with zinc transporters, particularly ZIP6, ZIP7, and ZIP10, along with MTs and ZnT2, having profound effects on cellular processes like cell migration, cell viability, and apoptosis. These molecules not only impact zinc homeostasis within the cancer cells but also modulate important signaling pathways and cellular responses to hypoxic environments, thereby influencing the progression and outcome of the disease.

Prostate cancer

Of all the soft tissues in human bodies, normal and hyperplastic prostate tissues have the highest concentrations of zinc accumulation. 351 On the other hand, zinc concentrations detected in prostate cancer were greatly reduced. 352 The peripheral zone, which is found to serve as the origin of prostate cancer, is responsible for secreting prostatic fluid. An essential and distinctive component of this fluid is the remarkably high concentration of citrate. 353 , 354 , 355 Traditionally, citrate is oxidized in the tricarboxylic acid (TCA) cycle, while high cellular zinc levels in normal prostate cells prevent this process by inhibiting the activity of mitochondrial aconitase (m-aconitase) 356 (Fig. 5 ). Furthermore, to preserve normal prostate function, physiological zinc levels induce apoptosis through various mechanisms in prostate cells. These include upregulating the Bax/Bcl-2 ratio in the mitochondria, 357 inducing HIF-1α degradation, 358 and involving with NF-κB pathway 359 (Fig. 6 ). Besides, zinc is also involved in the inhibition of invasion and adhesion in malignant prostate cancer cell through several ways: strongly prevents the enzymatic activity of prostate-specific antigen (PSA) and suppresses the invasion of LNCaP cells, 360 reduces the expression of vascular endothelial growth factor (VEGF), 361 interleukin (IL)-6, IL-8, matrix metalloproteinase-9 (MMP9), intercellular adhesion molecule-1 (ICAM1), diminished the activity of urokinase-type plasminogen activator and aminopeptidase N (AP-N) 362 (Fig. 5 ). Unfortunately, prostate cancer cells have significantly lower zinc levels, and hence they are unable to inhibit m-aconitase activity, ultimately resulting in the inability to obtain normal prostate fluid with citrate in tissue. 363 Also, m-aconitase activity can contribute to the proliferation and migration of prostate cancer cells. 364 Indeed, the low zinc concentration in malignant cells possesses mechanisms such as ZIP downregulation and ZnT upregulation.

The molecular mechanism of zinc transporters and MTs in PC. ZIP4 promotes PC carcinogenesis mainly through two transcription factors, CREB and ZEB1. ZEB1 promotes the procession of EMT by suppressing the expression of ZO-1 and CLDN1 and inducing the transcription of ITGA3. Moreover, the ZEB1 induces integrin α3β1 to phosphorylate JNK and ultimately blocks ENT1, a gemcitabine transporter, which results in chemoresistance. Besides, cellular zinc released by MT1G inhibits NF-κB, suppressing PC chemoresistance. CREB transcripts miR-373 to increase metastasis, invasion, and proliferation by activating the Hippo pathway yet inhibiting the expression of TP53INP1 and CD44 . Besides, PHLPP2, inhibited by miR-373, forms a malignant cycle through the suppression of CREB. However, the small molecule, circ ANAPC7, can block miR-373. As a target for PHLPP2 dephosphorylation, AKT increases the proliferation by upregulating cyclin D1 and promotes muscle wasting by phosphorylating STAT5. Another CREB-mediated downstream promoting muscle wasting is RAB27B. Mechanically, RAB27B promotes the release of HSP70 and HSP90 from MVB. Additionally, the CREB-mediated IL-6/STAT3/cyclin D1 pathway leads to proliferation in PC. ZIP4 could restrain apoptosis by inhibiting the activity of caspase9 and caspase7. The expression of ZIP3 is reduced by RREB-1. ZO-1, zonula occludens-1; ITGA3, integrin subunit alpha 3; JNK, c-Jun N-terminal kinase; MVB, multivesicular body; EMT, epithelial-mesenchymal transition

ZIP1 predominantly localizes at the basolateral membrane. Both normal and hyperplastic prostate glandular epithelial cells have in situ expression of ZIP1, where it transports zinc from the plasma into the cell. 365 , 366 In most cases, it plays a predominant role in zinc accumulation in benign prostatic hyperplastic epithelial cells. In contrast, ZIP1 is downregulated in malignant cells, resulting in the inability to accumulate zinc. 367 , 368 , 369 Therefore, prostate cancer can be characterized as a ZIP1-deficient tumor. 370 The expression of ZIP1 and ZIP2 detected by RT-in situ-PCR was lower in African Americans’ prostate epithelial cells than in Caucasian men, which could be involved in the higher susceptibility of African-Americans to prostate cancer. 367 Interestingly, overexpression of ZIP1 can sensitize the tumorigenic prostate epithelial cells (RWPE2) to tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL)-mediated apoptosis. 371 It was shown that the core promoter regions, contributing to the regulation of ZIP1 expression, are modulated by SP1 as well as CREB. 372 RREB-1, the downstream of ERK in the Ras/Raf/MAPK pathway, was upregulated in prostate cancer progression. 373 , 374 , 375 The inhibition of ZIP1 expression in prostate cancer implicates the mobilization of RREB-1, which could become one of the possibilities for the downregulated expression of the zinc transporter in malignant prostate disease 376 (Fig. 5 ). Besides, ZIP1-mediated rapid increase of zinc levels seems to be androgen-dependent. 377 Furthermore, by acting as an androgen cell membrane receptor, ZIP9 facilitates the mechanism of testosterone-dependent apoptosis in prostate carcinoma. 378 , 379

Unlike ZIP1, ZIP2 and ZIP3 are hardly localized to the basolateral membrane, both of which are mainly constrained to the apical membrane of the prostate tissue. 380 Studies on cell lines suggest that the functional role of ZIP2 and ZIP3 is to transport or reabsorb zinc from prostatic fluid back to the epithelium, 14 , 381 rather than accumulating cellular zinc from the blood circulation, which is the primary function of ZIP1. 382 Human prostate tissue sections examined by immunohistochemistry examination show significantly reduced regulation of ZIP2 and ZIP3 in adenocarcinoma glands, leading to dysfunction in accumulating zinc. 371 , 380 , 383 Thus, it is reasonable to propose that ZIP1, ZIP2, and ZIP3, all of which belong to the ZIP family, function as tumor suppressor genes in prostate carcinogenesis.

Regarding the ZnT transporter family, ZnT4 is five times higher in prostate cancer as measured in normal tissues. 111 Furthermore, ZnT4, as well as ZnT10, is highly induced by the HOXB13. 384 The introduction of exogenous HOXB13 decreases intracellular zinc levels in prostate cancer cells and activates NF-κB signaling, which promotes prostate cancer invasion. In addition, ZnT4 mRNA was found to be overexpressed in tumor samples acquired through radical prostatectomy versus normal tissues. 385 Interestingly, ZnT5 was also expressed at high levels in human prostate tissue. 386 Further study of the mechanistic impact of altered zinc transporter expression levels on prostate carcinogenesis has important implications for clinical treatment.

Additionally, studies investigating the relevance between MT expression and pathological/malignant conditions are severely limited in the prostate, and the regulatory mechanisms of zinc on MTs expression in prostate cells remain unclear. MT1/2 downregulation has been observed in benign prostatic hyperplasia (BPH), PC-3 cells, and malignant tissues of the human prostate. MT1/2 expression is notably enhanced by zinc therapy in both PC-3 and BPH cells, coincident with the restoration of intracellular zinc concentrations. Specifically, in BPH cells, MT3, acting as a growth inhibitory agent, was identified, and its levels were elevated by zinc. Furthermore, the expression of MT3 serves as a distinctive feature exclusively found in BPH cells. 387 MT1h, one of the components of the MT1 family, is commonly decreased in prostate cancer. The heavy methylation of its promoter has been observed. MT1h exerts its role as a tumor suppressor by activating euchromatin histone methyltransferase 1 (EHMT1), which leads to histone methylation and potentially suppresses gene expression. 388

Pancreatic cancer (PC)

Despite tremendous research efforts in the past few years, PC remains one of the most devastating diseases and has the highest fatality rate among all cancers. 389 Accumulating evidence indicates a strong correlation between zinc transporters and PC growth and progression. 75 , 312 , 390 , 391 , 392 However, the zinc levels and the molecular mechanisms through which zinc transporters regulate cancer growth in PC are not yet fully understood. Therefore, it is essential to study the effects of zinc transporters in PC carcinogenesis.

Overexpression of ZIP4 is widely described in human PC tissues and cell lines, contributing to tumor growth. 75 , 393 , 394 , 395 , 396 , 397 , 398 , 399 Obviously, the potential role by which ZIP4 is involved in PC growth and migration may be multifaceted. Knocking out ZIP4 is able to suppress the proliferation of PC through reducing cyclin D1 expression, 393 which serves as the downstream target of CREB/miR-373/PHLPP2 and CREB/IL-6/STAT3 pathway. Both pathways are activated by the overexpression of ZIP4, leading to PC cell proliferation 400 (Fig. 6 ). ZIP4 contributes to the mediation of metastasis in addition to the proliferation of PC cells. ZEB1 is the most critical EMT-associated transcription factor in PC, promoting stemness, invasion, and metastasis of PC. 401 Significantly, ZIP4 induces the expression of ZEB1, which mechanically is through phosphorylated STAT3. 395 Another report suggested that ZIP4 activates PC migration and invasion by mediating ZEB1 inhibition of ZO-1 and Claudin-1 expression 394 (Fig. 6 ). Additionally, ZIP4 is able to induce the expression of YAP1 by stimulating a miR-373-LATS2 pathway in PC, promoting organ formation and cell adhesion through the increasing expression of ITGA3. 74 Notably, the upregulation of ZEB1 inhibited expression of the gemcitabine transporter via ITGA3/ITGB1/α3β1 signaling and c- JNK pathway, which leads to chemoresistance both in vitro and in vivo. 395 Moreover, ZIP4 has a notable role in PC-related cachexia, where it facilitates the release of HSP70 and HSP90 via extracellular vesicles, thereby stimulating muscle atrophy. 75 Whereas the CircANAPC7 inhibited ZIP4/miR-373 mediated muscle wasting partially through STAT5/TGFβ signaling in PC. 400 These findings suggest that ZIP4 might serve as a potential PC diagnosis and therapy target (Fig. 6 ).

It could infer that aberrant overexpression of ZIP4 elevates zinc concentrations in PC cells. Using the nude mice model with subcutaneous xenograft, a study found that 80% more zinc was detected in the tumors implanted with ZIP4 stably overexpressed MIA-ZIP4 cells compared with the normal group. 393 However, clinical and preclinical indications disclose that zinc is persistently and significantly reduced in the early stage of PC compared with the normal or benign pancreas tissues, which is an essential malignant event. 402 Indeed, the reduction in zinc levels in pancreatic intraepithelial neoplasia (PanIN) lesions and malignancy is attributed to the downregulation of Ras responsive element binding protein 1 (RREB-1) and the silencing of ZIP3. 380 , 390 , 402 Another study has proved that PC cells are vulnerable to high zinc concentrations. The exposure of PC cells to physiological concentrations of zinc (0.01–0.5 mM) can lead to cytotoxic cell death, which is characterized by up-regulation of the zinc transporter ZnT1 gene expression. 312 Another study revealed that higher levels of zinc chloride (>50 μM) significantly reduced the proliferation of MIA-ZIP4 cells, suggesting that zinc activated the proliferation of PC cells only at comparatively low concentrations. 393 Besides, zinc provided by MT may be working with transcription factors. Research has shown that MT1G plays a crucial role as a tumor suppressor in pancreatic cancer stem cells. The downregulation of MT1G, caused by hypermethylation of its promoter, is associated with the maintenance of pancreatic cancer stemness. Mechanistically, MT1G exerts a negative regulatory effect on NF-κB signaling and facilitates the degradation of the NF-κB p65 subunit by upregulating the expression of E3 ligase TRAF7, consequently suppressing PDAC stemness. 403

Apparently, zinc is essential for cellular function, growth, reproduction, and metabolism. Thus, normal cells have evolved homeostatic mechanisms to maintain their normal required zinc levels and prevent the potential adverse effects of excessive zinc concentrations. However, the malignant cell has lost these normal protective conditions. PC cells require excess zinc to support proliferation and, on the other hand, avoid the adverse effects of zinc through other regulatory mechanisms.

Colorectal cancer (CRC)

Notably, a meta-analysis of human studies indicated that higher zinc intake was inversely associated with the overall risk of digestive tract cancers, especially for CRC. 404 It has been reported that zinc can inhibit the proliferation of colon cancer cells by arresting the cell cycle in the G2/M phase and disrupting the microtubule stability of cell-cell communication. 405 Hence, zinc transporters could be involved in GI disorders.

By bioinformatic analysis of microarray data in the GEO database, it has been identified that ZnT10 is one of the ten recommended candidate genes associated with CRC. 406 Consistently, a recent study reported ZnT10 as a methylation marker in the CRC, and the methylation epigenotype significantly correlated with KRAS and BRAF mutation in CRC. 407 In contrast, reduced expression of ZnT10 is associated with aggressive tumor phenotypes and poor patient outcomes in CRC. 408 ZnT10 acts as a competitive endogenous RNA for miR-21c to upregulate tumor suppressor gene APC expression, thus inhibiting CRC progression and metastasis. 408

Additionally, ZnT9 is the coactivator of β-catenin-mediated gene transcription, 409 , 410 which serves as the critical event in the Wnt signaling pathway and the development and progression of colon cancer. 411 Notably, the binding of ZnT9 and β-catenin can be competitively replaced by KCTD9, a tumor suppress gene which is negatively correlated with the clinical CRC stage, thus substantially inhibiting the transcription of downstream oncogenes, including MYC , CCND1 , and MMP7 409 (Fig. 7 ). In fact, ZIP7 also plays a crucial role in intestinal epithelial self-renewal. 187 Colorectal tumors have higher expression levels of ZIP7 than normal colon tissues. 412 It was demonstrated that the knockdown of ZIP7 induced G2/M cell cycle arrest and promoted apoptosis in colorectal cancer cells. 413 Furthermore, the downregulation of ZIP7 promoted the cleavage of PARP, enhanced the expression of Bad, Caspase-9, and cleaved-Caspase-3, and suppressed Bcl-2 expression in CRC. 413

The molecular mechanism of zinc transporters and metallothioneins in CRC, GC, and ESCC. In CRC, the binding of ZnT9 and β-catenin triggers the transcription of CCND1 , MYC , and MMP7 , resulting in proliferation and migration. KCTD9 can replace the binding of ZnT9 and β-catenin. Moreover, ZIP14 contains two alternative splicings, ZIP14-4A and ZIP14-4B. ZIP14-4B is upregulated by SRPK1 and SRSF1, two downstream targets of Wnt signaling, leading to increased Cd 2+ uptake. Concerning the GC microenvironment, ZIP7 is the upstream target of the AKT/mTOR signaling pathway. In GC, autophagic degradation of MT1E, MT1M, and MT1X initiated by USP2-E2F4 interaction leads to increased intracellular zinc storage vesicles, promoting GC cell growth. In contrast, MT2A inhibits NF-κB by releasing cellular zinc and thus ultimately suppresses GC cell proliferation. As for ESCC, ZIP6 activates PI3K/AKT and MAPK/ERK signaling pathways, which leads to the overexpression of downstream oncogenes such as MMP1 , MMP3 , MYC , and SLUG . Meanwhile, the cellular zinc released by MT2A promotes the oncogenic function of IGFBP2. NF-κBIA, NF-κB inhibitor alpha; IGFBP2, insulin-like growth factor binding protein 2

Alternative splicing is a critical step in generating protein diversity, and its misregulation has been observed in carcinogenesis. 414 , 415 , 416 Notably, alternative splicing of ZIP14 was found to be regulated by the Wnt pathway in CRC, most likely through the regulation of SRPK1 and SRSF1 417 (Fig. 7 ). ZIP14 contains two mutually exclusive exons, 4 A and 4B, and the ratio of exon 4 A/4B was significantly reduced in adenomas and cancers, which may be used as a tumor marker for identifying CRC and precancerous lesions. Specifically, the exon 4B isoform of ZIP14 is found to have an eightfold higher affinity for Cd 2+ than the exon 4 A isoform, which is known as a potent carcinogen. 99 Moreover, Cd 2+ has been found to influence several cellular processes, including apoptosis, differentiation, and cell growth, especially the inhibition of DNA mismatch repair, 418 , 419 thus setting off CRC carcinogenesis.

Beyond the roles of ZIP and ZnT transporters in CRC, our review extends to proteins such as MTs that regulate cellular zinc metabolism. Intriguingly, these MTs often act as tumor suppressor genes in CRC. A notable correlation between low MT1B, MT1H, or MT1L expression and an increased risk of adverse outcomes was identified. 420 Additionally, a distinct four-gene model, consisting of MT1F, MT1G, MT1L, and MT1X, effectively predicted survival and CRC prognosis. It has been reported that zinc potently enhances MT expression and is cytotoxic to cancer cells. 421 MT2A expression decreased in colorectal cancer and was linked to the patient’s tumor M stage. 422 , 423 The present research has mechanistically illustrated that MT2A upregulation promoted the expression of phosphorylated MST1, LATS2, and YAP1, which consequently inhibited the Hippo signaling pathway and controlled CRC cell proliferation and liver metastasis. 422 However, it is unclear whether the role of MT in controlling the MST1/LATS2/YAP1 signaling pathway depends on its regulation of zinc. Thus, the role of zinc and its regulatory mechanism in CRC requires further in-depth investigation.

Gastric cancer (GC)

In GC studies, the relationship between zinc intake and GC is contradictory. On the one hand, a large number of studies point out that lower zinc intake may increase the risk of GC. 424 , 425 , 426 For example, Cixian and Linxian are one of the higher-risk areas for upper GI cancer both in China and worldwide, where individuals have a zinc intake below the recommended daily allowance and higher incidence and mortality rates of GC than that of other regions. 427 , 428 , 429 However, a meta-analysis revealed that zinc intake was significantly associated with GC risk in Asia but not in America and Europe. 404 The heterogeneity in the results of zinc intake associated with GC risk may be due to the differences in the expression background of zinc transporters.

Multiple bioinformatic approaches revealed that high expression of five genes ( ZnT1 , 5-7 , and 9 ) was significantly correlated with better overall survival (OS), first progression survival (FPS), and post-progression survival (PPS), while upregulated ZnT2-4 , 8 , and 10 expressions was markedly associated with poor OS, FP, and PPS. 430 In addition, ssGSEA analysis indicated that SLC30 family genes were closely associated with the infiltration of immune cells, indicating that the ZnTs induced tumorigenesis partly because of immune infiltration. 430

In the GTEx and TCGA datasets, ZIP10 was highly expressed at the mRNA level in malignant GC cells compared to normal and adjacent non-tumor samples. 431 A previous study has demonstrated that ZIP10 expression was correlated with STAT activation in B cell lymphoma samples. 137 In GC, the novel natural product inhibitor of STAT3 termed XYA-2 might exert its anticancer activity by synergistically inhibiting the expression of MYC and ZIP10, two downstream genes of STAT3 in vitro and in vivo. 431 Meanwhile, ZIP6, another downstream target of STAT3, is involved in cancer development by forming a heterodimer with ZIP10. 157 Besides, the ZIP7 mRNA level was increased in both GC tissues and cell lines, which boosted cell proliferation and migration, while inhibiting apoptosis in GC. 432 Specifically, ZIP7 was negatively regulated by miR-139-5p and positively regulated GC development through Akt/mTOR signaling pathway, suggesting that ZIP7 may be a candidate target gene for GC treatment (Fig. 7 ).

Alarmingly, reduced expression of MT1 or MT2 has been observed in GC, a pattern correlated with worse prognoses. 433 There has been an observed decrease in MT2A and myeloid zinc-finger 1 (MZF1) expression in clinical specimens that are undergoing malignant transformation of the stomach. 434 Intriguingly, an important role played by zinc accumulation in controlling cancer through autophagy flux has been reported. 435 Autophagic degradation of MT1E, MT1M, and MT1X, initiated by E2F4 in GC, leads to an increase in zinc-stored vesicles within autophagosomes. This, in turn, lowers the levels of free intracellular zinc and facilitates the growth and invasion of GC cells. These findings offer a novel insight into how autophagy modulates zinc homeostasis in cancer cells. 48 In line with this, recent evidence has indicated that MT1M has the ability to dampen the malignancy and stem cell-like characteristics of GC by inhibiting GLI1, a component of the Hedgehog signaling pathway, known for its numerous zinc finger domains. 436 Besides, the MT1 gene cluster has been found to be hypermethylated in EBVaGC, suggesting redundant anti-EBV roles among various MT1 genes. 437 MT1 proteins provide cellular protection against OS via their antioxidant properties, 438 which account for their anti-EBV functions.

Furthermore, in human GC cell lines and primary tumors, the transcription factor MZF1 has been found to be epigenetically silenced, a finding associated with MT2A. MZF1 serves to deter gastric carcinogenesis by associating with MT2A to bind to the NFKBIA promoter (Fig. 7 ). Notably, this tumor-suppressive effect can be stimulated by diallyl trisulfide (DATS), a compound derived from garlic known to thwart the progression of GC. 439 In keeping with the ability of zinc to inhibit NF-kB activation in cancer cells, 440 , 441 , 442 zinc chelation likely plays a part in the anti-GC activity of the MT2A/MZF1–NF-kB pathway mediated by DATS. MT2A simultaneously controls zinc-binding proteins by adding or removing zinc and is transcriptionally inducible by these proteins to target its promoter region, which contains numerous regulatory elements, such as the MRE. 434 Therefore, the diminished expression of MZF1/MT2A significantly associates with the malignancy of GC and poor patient outcomes. Additionally, MT2A hinders cell growth via apoptosis and G2/M arrest, negatively influencing the NF-κB pathway through upregulation of IκB-α and downregulation of p-IκB-α and cyclin D1 expression. 298 ApoMT (metal-free MT) has been identified as a potential agent for extracting zinc from NF-κB, thereby rendering the NF-κB-mediated transcriptional activity inactive due to zinc chelation. 443 In conclusion, targeting GC by interfering with zinc metabolism appears to be a viable approach (Fig. 7 ).

Esophageal squamous cell carcinoma (ESCC)

Another essential type of digestive tract tumor is ESCC. Actually, ZD in dietary potentiates the effects of specific nitrosamines that act as esophageal carcinogens in rodents. 444 A study using x-ray fluorescence to measure zinc concentrations in tissues demonstrated that zinc concentration is inversely associated with the risk of incident ESCC. 445 Zinc replenishment rapidly induced apoptosis in esophageal epithelial cells and thereby substantially reduced the development of ESCC. 446

However, ZIPs, the proteins that translocate Zinc into cells, are associated with ESCC. Immunohistochemical staining of ESCC tissues showed that higher expression of ZIP6 predicted unfavorable prognosis in individuals with advanced ESCC. 447 ZIP6 overexpression is an “early” or “intermediate” event in the ESCC malignant progression, indicating that ZIP6 could serve as an early detector of high-risk subjects and prognostic biomarker. 448 Cheng et al. revealed that overexpression of ZIP6 or elevated intracellular zinc levels in cancer cells substantially activated the PI3K/AKT and MAPK/ERK signaling, which upregulated downstream oncogenes such as MMP1 , MMP3 , MYC , and SLUG . 449 This up-regulation of these molecules may be the underlying mechanism for the aggressive phenotypes of ESCC with ZIP6 overexpression (Fig. 7 ).

Similarly, studies suggested that ZIP5 protein and mRNA expression was highest in ESCC, intermediate in paraneoplastic tumors, and lowest in normal tissue. 450 Kumar et al. found that the dysregulation of zinc homeostasis in esophageal tumorigenesis is mainly reflected in the upregulation of ZIP5 and the downregulation of the zinc metabolism protein MT1G using cDNA microarray. 451 Besides, the downregulation of ZIP5 decreased the expression of COX2 and increased the expression of E-cadherin in the KYSE170K xenografts. 452 COX2 is an essential molecular basis for cancer progression, which promotes the proliferation and invasive ability of tumors and inhibits cancer cell apoptosis. 453 Collectively, knocking down ZIP5 by small interfering RNA might be a novel therapeutic strategy for ESCC with ZIP5 overexpression. Although some studies have shown that zinc ion intake might suppress tumor growth, overwhelming reports focus on the promoting role of zinc in tumor initiation and development, or even driving metas44tasis. MT2A, acting as a zinc donor, induces IGFBP2 and inhibits the expression of E-cadherin through a zinc finger protein. 454 , 455 Recombinant IGFBP2 promoted migration and invasiveness of ESCC cells via NF-κB, Akt, and Erk signaling pathways.

In pan-cancer copy number variation (CNV) and mutation analyses from the TCGA database, 456 most of the SLC30 and SLC39 family genes demonstrated gene amplification, especially SLC30A8 , SLC30A1 , SLC30A10 , SLC39A1 , and SLC39A4 . Notably, the gene for SLC30A8 and SLC39A4 amplification was co-occurring in almost all cancer patients. Interestingly, the cases with SLC39A14 deletion appear to be more than those with amplification (Fig. 8 ). Although ZIPs are more commonly regarded as oncogenes in cancer, prostate cancer is an exception. Studies also suggested that the function of the zinc transporters may be contradictory among different cancer types. As we delve into the gene alterations in MTs, our attention is captured by the astonishingly consistent variations observed among all MTs members (Fig. 8 ). Notably, the compelling set of data from representative tumor patients showcases the remarkably homogeneous trends in gene alterations among all MTs members. Such changes predominantly encompass amplifications and deep deletions, implying pivotal roles for MTs in the context of cancers. Despite the similar gene alteration trends, disparate mRNA expression profiles are observed for different MTs members. This intriguing observation suggests the involvement of intricate transcriptional regulatory mechanisms governing MTs genes. The diversity in mRNA expression levels might arise due to a myriad of factors, potentially linked to cellular context, tissue specificity, and even cancer types. Thus, research on zinc transporters and MTs in tumorigenesis is still a long way to go.

Genetic and mRNA alterations of zinc transporter and MT family genes in pan-cancer patients. The upper figure illustrates the gene alterations of zinc transporters. Out of the queried pan-cancer samples, 1526 (59%) showed copy number aberrations, mutations, and mRNA expression changes. The lower figure displays the gene alterations of MTs, where 324 (13%) of the queried pan-cancer samples demonstrated copy number aberrations, mutations, and mRNA expression changes. This diagram includes a total of 30 cancer types, marked with different colors. The data source is from the pan-cancer analysis of whole genomes dataset in cbioportal ( https://www.cbioportal.org/study/summary?id=pancan_pcawg_2020 )

Other cancers

Zinc homeostasis disruption has been observed in patients with various types of cancers. Studies have highlighted the significance of zinc-containing enzymes called matrix metalloproteinases (MMPs), which can be activated by zinc. 457 , 458 ZIP4, in particular, has been shown to regulate the expression of MMP2 and MMP9, influencing zinc concentration and promoting invasiveness and migration of hepatoma cells. 397 Notably, ZIP4 expression is linked to post-liver transplantation outcomes in HCC patients, making it a potential treatment target and prognostic marker for liver transplantation in HCC cases.

Besides, ovarian cancer, the most lethal gynecologic malignancy, exhibits rapid progression and widespread metastases. 459 Of note, ZIP13 was found to promote the proliferation, invasion, adhesion, and metastasis of ovarian cancer cells in vitro and in vivo. 73 The underlying mechanisms involve intracellular zinc distribution disruption and activation of the Src/FAK pathway, ultimately leading to ovarian cancer metastasis.

Drosophila melanogaster serves as a powerful model for cancer biology studies. Drosophila ZnT7 (dZnT7) acts as a tumor suppressor, negatively regulating JNK signaling. 460 dZnT7 knockdown induces JNK activation, promoting both cell-autonomous and nonautonomous autophagy, ultimately resulting in tumor overgrowth and migration.

Additionally, ZIP9 activation, through testosterone binding, induces an increase in cytosolic zinc in melanoma cells, thereby promoting cancer proliferation. 461 In gliomas, MT3 plays a key role in autophagy flux regulation via zinc-dependent lysosomal acidification, 435 contributing to glioma cell resistance to irradiation treatment. Targeting MT3 may thus enhance the efficacy of irradiation treatment. By elucidating the disruption of zinc homeostasis and its implications in cancer progression, these findings provide valuable insights into potential therapeutic strategies for diverse cancer types. Further research in this field may pave the way for improved cancer treatment and management.

Cellular zinc metabolism in cardiovascular disease

Noncommunicable diseases, such as cardiovascular disease (CVD) and cancer, are the leading causes of death worldwide. 462 The correlation between zinc and CVDs is a complex and multifaceted topic. Evidence suggests that zinc may be protective against certain CVDs, although the exact mechanisms are not fully understood. 270 , 463 , 464 Here, we focus on elucidating the crucial involvement of zinc in the progression of CVDs, specifically with regard to atherosclerosis (AS), diabetic cardiomyopathy, myocardial ischemia/reperfusion (I/R) injury, and heart events.

Atherosclerosis (AS)

Hyperlipidemic environments and inflammatory factors are known to significantly contribute to the development of AS. 465 Recent research highlights the critical role of ZD in the progression of this condition. 270 Zinc exerts influence on various characteristic aspects of AS, including increased apoptosis and disrupted NO levels. NO, synthesized in endothelial cells (ECs), acts as an essential endothelium-derived vasodilator. Reduced availability of NO occurs when there is a decrease in the expression or activity of endothelial NO synthase (eNOS), actively participating in the atherogenic process. 466 Additionally, it has been suggested that reduced NO generation in atheroprone regions, combined with increased ZnT1 and MT expression, may lead to decreased intracellular free zinc. 467 Studies using Zip13-KO mice have shown elevated levels of the cardiac fibrosis marker Col1a1 and the vascular inflammation-related gene eNOS, indicating the physiological importance of ZIP13 in maintaining cardiovascular homeostasis by resolving inflammation and stress response. 468

Moreover, the induction of EC apoptosis in response to oxidative stress is a characteristic atherogenic trait. Zinc is also associated with apoptosis and proliferation in vascular smooth muscle cells (VSMCs), 469 , 470 the primary contributors to the composition of atherosclerotic plaques. The regulators ZnT3 and ZnT10 play crucial roles in VSMC senescence and are susceptible to downregulation by Ang II and zinc. 471 Ang II signaling pathways become activated with age and contribute to developing AS and vascular senescence. 472 Interestingly, decreased catalase expression is observed, leading to ROS accumulation and induction of senescence. 471 ZnT3 and ZnT10 work to prevent increases in ROS levels by modulating the expression of catalase.

Myocardial ischemia/reperfusion (I/R) injury

Myocardial ischemia/reperfusion (I/R) injury is a prevalent cardiovascular condition associated with a high mortality rate. 473 Recent studies have revealed the importance of zinc homeostasis in cardiomyocytes during reperfusion, as zinc loss upon reperfusion contributes to I/R injury. 474 The crucial role of ZIP transporters in maintaining zinc homeostasis has been demonstrated, with ZIP2 playing a significant role in this process. 475 Deletion of the ZIP2 gene notably intensified myocardial I/R injury, whereas upregulation of ZIP2 demonstrated the potential to mitigate I/R injury. These findings suggest that ZIP2 exerts a cardioprotective effect against I/R injury by restoring zinc homeostasis. 475 Additionally, ZD has been shown to activate STAT3 through ER stress-induced Ca 2+ release and subsequent CaMKII activation, enhancing the transcriptional activity of ZIP9 and protecting against cellular ZD. 476

ZIP7 upregulation, on the other hand, hinders the accumulation of PINK1 and Parkin in mitochondria by increasing zinc outflow to the cytosol, contributing to the genesis of myocardial reperfusion injury by inhibiting mitophagy during reperfusion. 477 Consequently, the upregulation of ZIP7 is considered a significant feature of myocardial reperfusion injury and may present a novel therapeutic target for myocardial reperfusion injury and other cardiac diseases caused by oxidative stress or mitochondrial dysfunction.

Endogenous ZnT-1 has been shown to have a substantial protective effect against I/R injury, which is mediated by the C-terminal domain of the protein through the activation of Ras-ERK signaling. 478 Additionally, ZnT-1 serves various functions, such as binding to Raf1 and triggering the ERK cascade. 479 , 480 Additionally, it hinders LTCC activity by interacting with the β-subunit of the voltage-dependent calcium channel. The significance of ERK cascade activation in promoting cell survival after I/R injury has been extensively recognized. 481 Recent evidence suggests that nuclear factor (erythroid-derived 2)-like 2 (NRF2) activation/overexpression increases total zinc content in HCAEC with minimal changes in HCASMC, consistent with observed changes in ZnT1 and MT protein expression. 482 This finding further highlights the complex interplay between zinc, ROS, and endogenous antioxidant defenses regulated by NRF2.

Diabetic cardiomyopathy (DCM)

DCM is a prevalent and severe complication of diabetes. A link between systemic ZD and the increased incidence of diabetes and diabetic cardiovascular complications has been established. Notably, in diabetic mice, zinc supplementation has been shown to significantly protect against the development of DCM through the induction of cardiac MT. 483 , 484 , 485 , 486 MT has proven effective in countering cardiac fibrosis under stress conditions like diabetes and nicotine exposure. 484 , 487

MTs offer cardiomyocytes protection primarily through zinc-dependent antioxidant effects. During the early stages of diabetes, cardiac mitochondria experience cytochrome c release-dependent apoptosis. However, MT substantially inhibits this early cardiac apoptosis caused by diabetes by suppressing mitochondrial oxidative stress, particularly the depletion of GSH, which significantly prevents the development of DCM. 483 Moreover, MT suppresses Ang II-induced NOX-dependent nitrosative damage and cell death in both nondiabetic and diabetic hearts early in the injury process, effectively preventing the later development of Ang II-induced cardiomyopathy. 488 Furthermore, MT ameliorates ROS generation and cardiac fibrosis despite persistent cardiomyocyte contractile and intracellular Ca2þ derangement. 489 Both MT overexpression and direct MT administration can reduce DCM by suppressing peroxynitrite-derived nitrosative damage and ROS production in diabetic hearts. 490

Recently, it has been demonstrated that zinc-induced cardiac endogenous antioxidant MT blocks TRB3 induction, thereby preserving Akt2 signaling and preventing DCM. The development of pharmaceutical inducers of cardiovascular MT holds promise as a preventive measure against cardiomyopathy in diabetic patients. 491 In conclusion, the induction of MTs presents a potential therapeutic approach for preventing diabetic DCM.

Heart event

The zinc level in heart tissues is approximately 1 g or less, and it has been shown to have a positive correlation with ejection fraction in humans. 492 At a concentration of 1 nM, zinc can directly activate RyR2, which has a much higher affinity for zinc than Ca 2+ (about three-fold), providing an essential mechanistic explanation for the association between zinc dyshomeostasis and certain cardiomyopathies. 493 , 494 ZnT-1 is an endogenous negative regulator of the LTCC, particularly in the heart, where it appears to participate in cardiac electrical remodeling following atrial fibrillation. Increased ZnT1 expression is observed in patients with atrial fibrillation. 495 Mechanically, ZnT-1 was demonstrated to regulate the LTCC by interacting with its regulatory α1-subunit, thus limiting the plasma membrane expression of the LTCC. 151

Furthermore, serum zinc levels could serve as a valid diagnostic indicator for acute myocardial infarction (MI). 496 Meta-analysis data indicates that a lower dietary zinc intake is associated with an increased prevalence of coronary artery disease (CAD), and there is a direct relationship between zinc status and MI. 496 ZIP13 is ultimately in charge of CaMKII mobilization, while the suppression of ZIP13 aggravates myocardial infarction through destabilizing mitochondrial signalings. 497 Moreover, with respect to calcific aortic valve diseases, which is one of the most widespread heart valve disorders, the expression of ZIP13 is markedly enhanced. Correspondingly, ZIP13 knocking down resulted in the inhibition of human valve interstitial cells in an in vitro calcification model. 498 Thus, alterations in ZIP13 expression may occur due to cardiac stress, which may induce CVDs or promote their pathogenesis. Additionally, it has been demonstrated that ZnT5 is associated with heart function, and its deficiency causes osteopenia and sudden cardiac death. 386

During cardiac hypertrophy, the expression of ZIP2 was downregulated. 499 Inhibiting ZIP2 leads to the induction of interferon regulatory factor (IRF) 7 expression, which, in turns, triggers the activation of ZIP2 development. As a result, IRF7 functions the role of a feedback regulator to modulate ZIP2 expression according to its activity. Based on serial transgenic mouse models, it has been confirmed that IRF7, IRF8, and IRF9 were anti-hypertrophy factors that are consistently down-regulated in cardiac hypertrophy and heart failure. 500 , 501 , 502 To conclude, leveraging ZIP2 to modulate cellular zinc metabolism could offer an innovative approach for treating these two diseases. 499

Besides, zinc emerges as a novel inhibitor of Calcific aortic valve disease (CAVD). 498 The ZnR/GPR39 is reduced in calcified aortic valves from patients with CAVD. The anti-calcific effect of zinc on human valve interstitial cells (hVIC) calcification is, at least in part, mediated through the inhibition of apoptosis and osteogenic differentiation via the GPR39-dependent ERK1/2 signaling pathway. Additionally, ZIP13 and ZIP14 play important roles in hVIC in vitro calcification and osteogenic differentiation. 498

Additionally, left ventricular noncompaction (LVNC) is a cardiomyopathy caused by arrested compaction, characterized by excessive trabeculation with deep intertrabecular recesses and thin compact myocardium. 503 ZIP8 has been identified as a crucial factor in ventricular trabeculation and compaction, revealing a potentially novel regulator of ventricular myocardial development. As such, it may be included in the list of genes worth screening in patients with ventricular noncompaction or other diseases involving dysregulation of ECM degradation. 503

In conclusion, the effects of zinc on cardiovascular disease are multifaceted. Understanding the mechanisms by which cellular zinc metabolism and regulatory mechanisms influence these processes has the potential to develop new strategies for the treatment of cardiovascular disease.

Cellular zinc metabolism in autoimmune diseases

Zinc plays various roles in autoimmune diseases, including its function as an effector of the immune system, inflammation, and metabolism. As mentioned previously, the ZIP family, ZnT family, and MTs act as crucial regulators of zinc levels and are involved in developing different autoimmune diseases, such as the production of autoantibodies and inflammatory responses.

One specific autoimmune disease is type 1 diabetes, characterized by the destruction of pancreatic β cells mediated by T cells. Additionally, individuals with type 1 diabetes exhibit circulating autoantibodies targeting several β cell autoantigens. 504 In 2007, researchers identified zinc transporter 8 autoantibodies (ZnT8A), 233 which have since been recognized as one of the four major islet autoantibodies along with GAD65 autoantibodies (GADA), 505 islet antigen-2 autoantibodies (IA-2A), 506 and insulin autoantibodies (IAA). 507 In prospective studies involving hereditary relatives at first-degree risk for individuals of type 1 diabetes, ZnT8A typically emerges around the age of 3-4 years and persists until the onset of clinical disease. 233 , 508 ZnT8A serves as valuable markers for childhood-onset type 1 diabetes. 509 It is noteworthy that ZnT8A usually develops later in young individuals compared to IAA and GADA. The presence of ZnT8A, as well as IA-2A and ZnT8A positivity, can identify individuals with prediabetes who are at a high risk of rapidly progressing to clinical type 1 diabetes. 510 , 511 Moreover, the HLA class I A*24 allele, which is implicated in increased predisposition to type 1 diabetes, negatively correlates with the presence of ZnT8A at and before diagnosis, taking into account the age at onset. 512 , 513

Studies have proved that CD8 + T cells in individuals with diabetes recognize a range of ZnT8 peptides in different regions of the protein, including the transmembrane/loop and C-terminal regions. 514 , 515 Furthermore, isolated CD8 + T cells from individuals with diabetes show greater secretion of IFN-γ when stimulated by ZnT8. 516 Most of the mature ZnT8A responses target the C-terminal region of the protein, while only 10% recognize the N-terminal region. 517 Within the C-terminal region, ZnT8A can specifically target amino acid 325 of ZnT8, and this specificity is determined by the SLC30A8 polymorphism rs13266634. 518 Interestingly, the higher frequency of ZnT8A in childhood-onset patients is primarily due to an increased number of patients with aa325-nonrestricted ZnT8A. Additionally, the amino acid encoded by the polymorphic codon 325 (Arg, Trp, Gln) plays a significant role in the humoral autoreactivity of this protein. 518 , 519

In addition to T cells, a clinical trial discovered novel cryptic B cell epitopes in the ZnT8 autoantigen, which showed reduced levels of naturally occurring autoantibodies in diabetes. 520 ZnT8A titers decreased rapidly following the initiation of diabetes, reflecting the continuous loss of β-cell mass. 511 , 521 Although type 1 diabetes is commonly linked to other organic-specific autoimmune endocrine diseases, little evidence exists for a linkage between ZnT8A and markers of Addison’s disease (21OHA), autoimmune thyroiditis (TPOA), pernicious anemia (ATP4A-A), or celiac disease (TGA). 522 These findings suggest that islet autoantibodies are not pathogenic in type 1 diabetes but rather a consequence of the immune-mediated destruction of β-cells. From a clinical perspective, reducing ZnT8 transport activity or down-regulating its cellular expression is proposed as an anti-diabetogenic strategy, mimicking the protective effect of SLC30A8 haploinsufficiency in humans. 523

As previously mentioned, ZnT3 is crucial for transporting synaptic vesicular zinc, which can impact various signaling pathways downstream. Previous studies have suggested that zinc release/influx may be an initial event in the production of ROS induced by NADPH oxidase activation in experimental autoimmune encephalomyelitis (EAE). In mice, gene deletion of ZnT3 reduces the clinical symptoms of MOG35–55-induced EAE. This improvement is accompanied by reduced demyelination and the infiltration of encephalitogenic immune cells in the spinal cord. Furthermore, ZnT3 gene deletion inhibits the formation of EAE-associated aberrant synaptic zinc patches, MMP-9 activation, and disruption of the blood-brain barrier. 524 Additionally, Penkowa and Hidalgo demonstrated MT2 could become a prospective treatment candidate in multiple sclerosis, since it reduced cytokine expression in the CNS and prevent apoptotic neuronal death in an EAE model. 525

Genome-wide association studies have revealed an association between the SNP rs13107325 in SLC39A8/ZIP8 and Crohn’s disease. 197 Furthermore, microarray data from rheumatoid arthritis (RA) patients have shown a significant increase in the expression of ZIP8 in peripheral monocytes compared to healthy controls. 526 Monocytes and macrophages play crucial roles in the pathophysiology of RA by delivering enhanced costimulatory signaling and producing proinflammatory cytokines. 527 Since ZIP8 is constitutively expressed in resting monocytes and macrophages, it suggests that ZIP8-mediated zinc influx promotes inflammatory conditions in RA. Therefore, ZIP8 may represent a potential therapeutic target for various inflammatory disorders.

In conclusion, the regulation of cellular zinc metabolism and the involvement of zinc transporters and MTs play crucial roles in autoimmune diseases. This provides valuable insights into potential therapeutic targets and strategies for managing these complex conditions.

Cellular zinc metabolism in infectious diseases

Zinc, a divalent metal, holds a critical role in host-pathogen interactions by influencing microbial growth, pathogenicity, and the host’s immune defenses. Within innate and adaptive immune cells, two distinct and contrasting zinc-dependent mechanisms exist to combat pathogen invasion: nutritional immunity and zinc toxicity. Notably, nutritional immunity is a mechanism employed by immune cells to reduce the availability of zinc in the host, thereby hindering pathogen growth. In parallel, an excessive increase in zinc content within monocytes can induce zinc toxicity in pathogens, leading to their apoptosis. This intriguing interplay of zinc-related pathways highlights its multifaceted impact on the host-pathogen dynamic.

On one hand, nutritional immunity serves as a mechanism employed by immune cells to reduce the availability of zinc in the phagosome or cytoplasm, limiting its access and creating a phenomenon that restricts essential transition metal ions, including iron, zinc, selenium, and manganese, at the host-pathogen interface. This nutrient limitation strategy starves the invading pathogens. 292 , 528 Notably, in vitro studies have demonstrated the potential of zinc limitation strategies to combat carbapenem resistance caused by zinc metallo-β-lactamases, as evidenced by the restoration of carbapenem susceptibility in Acinetobacter baumannii and improved survival in mice infected with Aspergillus fumigatus when pathogens were starved with zinc chelators. 529 , 530 , 531 , 532 This approach may serve as an adjunctive therapy for difficult-to-treat pathogens like Aspergillus fumigatus. Laser ablation inductively coupled plasma mass spectrometry (LA-ICP-MS) has revealed that tissue abscesses caused by Staphylococcus aureus exhibit significantly lower levels of detectable zinc compared to the high zinc levels in surrounding healthy tissue. 533 While the specific factors responsible for sequestering zinc within abscesses remain unknown, the absence of nutrient zinc within the abscess appears to represent an immune strategy to control infection. Interestingly, in response to zinc sequestration, bacteria have developed mechanisms to overcome this limitation by expressing high-affinity zinc transporters. These zinc uptake systems can be categorized into two groups. The first category includes zinc transporter families with homology to the highly affinity ZnuABC transport system of Escherichia coli . 534 Additionally, both N. gonorrhoeae and N. meningitides express a specific zinc-import system called ZnuC, ZnuB, and ZnuA to improve intracellular zinc status. 535 The second category of zinc transporters is analogous with the eukaryotic ZIP family transporters, but ZIP homologs are exclusively discovered in Escherichia coli . 534

On the other hand, in certain infections like Mycobacterium tuberculosis , the zinc content in the phagosome is excessively increased, leading to zinc intoxication of the pathogen. 536 When monocytes are stimulated with Mycobacterium bovis BCG cell wall, they induce ZIP8 expression, suggesting that extracellular zinc can be drawn in to fuel the host’s zinc poisoning strategy. 131 Nutritional immunity and metal intoxication are feasible immune strategies to limit pathogen growth and control infection. Nutritional immunity primarily affects enzymatic and metabolic functions, while metal overload contributes to the generation of ROS, reactive nitrogen species, protein mismetallization, and subsequent respiratory arrest. 533 , 537 , 538 , 539

In particularly, within macrophages, two lines of host defense are observed: zinc sequestration and zinc intoxication. Sequestration of zinc by MTs deprives pathogens of this essential nutrient, making them susceptible to killing by superoxide. 540 Infection of macrophages with M. tuberculosis triggers zinc intoxication in both the host and the intracellular bacteria, indicating that the host-pathogen interaction disrupts zinc homeostasis in both organisms. The cytokines TNFα and IFNγ promote the accumulation of zinc in the phagosome of Mycobacterium avium-infected mouse macrophages, and phagosomal zinc levels increase over time in response to infection with Mycobacterium tuberculosis. 541 M. tuberculosis infection also up-regulates ZnT1 expression in human macrophages, 542 which probably facilitates the increase of zinc levels in macrophage phagosomes in conjunction with M. tuberculosis . 543 , 544 Additionally, ZIP8 has been identified as a feedback controller of macrophage inflammatory responses. 196 Its expression is upregulated by LPS and TNF, and the mechanism involves direct regulation by the transcription factor NF-κB. LPS also up-regulates ZIP14 mRNA from primary human macrophages, which acts as a limiting inflammatory response. 545 Furthermore, M. tuberculosis possesses a counter-defense strategy that involves extruding incoming zinc via the P1B-type ATPase efflux pump, CtpC, to resist zinc toxicity. 542 Mutant bacilli lacking CtpC are highly sensitive to zinc, rapidly accumulate the metal, and are killed by human macrophages. Macrophages adopt a similar zinc intoxication mechanism to challenge non-pathogenic Escherichia coli , indicating that zinc poisoning is a general defense strategy against intracellular bacteria. 546 Mycobacterial infection causes a “burst of free zinc” within macrophages and increases the levels of zinc-binding proteins, MT1 and MT2, and ZnT1. 547 Although macrophages are not yet proven to be capable of metallotoxicity against pathogenic Neisseria species, it has been shown that these immune cells can enhance zinc accumulation in cytoplasm and phagocytic vesicles through ZIPs. 131 , 140 , 548 This suggests that host-induced zinc toxicity may be relevant to pathogenic Neisseria infection. Therefore, high levels of zinc within macrophages can directly exert bactericidal effects.

Above all, cellular zinc metabolism influences host-pathogen interactions through nutritional immunity and zinc toxicity, affecting pathogen growth and host defense mechanisms. Zinc modulation offers potential therapeutic targets in infectious diseases.

Cellular zinc metabolism in neurodegenerative diseases

Zinc homeostasis alterations have been suggested to be closely associated with the development of certain neurodegenerative diseases. 66 , 549 , 550 In patients with PD, AD, and amyotrophic lateral sclerosis (ALS), there is a significant increase in the zinc content within the cerebrospinal fluid. ZD, on the other hand, was demonstrated to impact neurogenesis as well as augment neuronal apoptosis, resulting in impaired learning and memory, highlighting the importance of elucidating the involvement of cellular zinc metabolism in the pathogenesis of these diseases.

Altered neuronal zinc handling plays a pivotal role in AD pathogenesis. Zinc released during neurotransmission was found to bind to amyloid-β peptides, accelerating the assembly of amyloid-β into oligomers that impair synaptic function. 551 Multiple studies indicate that ZnT3 is crucial for reducing the risk of AD by facilitating the excretion of neuronal zinc. 40 , 552 , 553 , 554 , 555 The expression level of ZnT3 in the cortex has been observed to decline with age in individuals with AD and in healthy individuals. 40 , 556 Additionally, a rare copy number variant of the ZnT3 gene may be involved in the monogenic determination of autosomal dominant early-onset AD. Metal chaperones such as CQ and PBT2, which maintain metal ion homeostasis, have been shown to restore cognition, elevate zinc levels in the hippocampus, and restore levels of key proteins involved in learning/memory and synaptic plasticity in ZnT3 knockout mice. 552 This raises the interesting question of whether metal chaperones could serve as an alternative zinc transporter. It has been found that other transporters, such as vGlut1, may compensate for the deficiency of ZnT3 by loading zinc into synaptic vesicles. 557 In turn, Lang et al. 558 demonstrated that overexpression of the Drosophila homolog of human ZIP1 leads to zinc accumulation in Aβ42-expressing fly brains, and inhibition of ZIP1 expression reduces Aβ42 fibril deposits and improves cognition 16. Zinc binding to amyloid-β is also influenced by MT3 released by astrocytes. Furthermore, the decreased extracellular levels of MT3 observed in AD may facilitate hypermetallation of amyloid-β by zinc. 559 A study utilizing microarray data from the human frontal cortex has shown that the expression of ZNT3 and ZNT4 significantly decreases with age, while the expression of ZIP1, ZIP9, and ZIP13 significantly increases. 67

In vitro observations have confirmed the high enrichment of zinc within senile plaques. AD patients exhibit changes in ZnT proteins (ZnT-1, ZnT-4, and ZnT-6) 5. ZnT1 and ZnT4 are expressed throughout the senile plaque, whereas ZnT3, ZnT5, and ZnT6 are localized to the periphery of the plaque. 560 ZnT10 mRNA expression is significantly decreased in the frontal cortex of patients with AD, 561 similar to the case in APP/PS1 mice. Dysfunction of ZnT10 may contribute to Aβ deposition and the formation of senile plaques. Recently, research has shown that ZIP9 plays a key role in the effects of DHT in APP/PS1 mice. 562 Specifically, ZIP9 influences the expression levels of synaptic proteins, including PSD95, drebrin, and SYP. It also affects dendritic spine density in the hippocampus. These changes are mediated through the ERK1/2-eIF4E signaling pathway, which in turn has an impact on learning and memory processes. Therefore, new experimental evidence suggests that androgen supplementation improves learning and memory in AD.

In addition to AD, alterations in intracellular zinc homeostasis are considered a critical factor in the development of PD. Overwhelming evidence supports the notion that excessive intracellular zinc levels are implicated in the development of the disease. 34 , 563 Zinc directly interacts with α-synuclein, a causative agent of PD and other neurodegenerative diseases, promoting its aggregation. 564 Furthermore, zinc released from corticostriatal terminals may predominantly contribute to the deleterious effects associated with motor and cognitive symptoms in PD, as it acts synergistically with glutamate. 207 Excessive glutamatergic corticostriatal transmission has long been recognized for its contribution to the development of PD symptoms and neurotoxicity, leading to neuronal degeneration.

The relationship between zinc levels and Huntington’s disease (HD) presents contradictory findings. Synaptic dysfunction significantly contributes to the pathogenesis of HD, 565 with vesicular zinc playing a significant role in synaptic function. 566 , 567 Specifically, increased levels of zinc have been measured in HD patients, suggesting that mutant Htt (mHtt) may disturb zinc metabolism. 568 mHtt decreased ZnT3 expression by suppressing the conjugation of Sp1 with ZnT3 promoter. 569 As a result, it downregulates vesicular zinc levels in the brains of N171-82Q HD transgenic mice. However, ZD was observed in the hippocampus and cortex of the R6/1 mouse model of HD. 570 Previous studies have demonstrated significantly higher zinc levels in the cerebrospinal fluid of patients with ALS. Likewise, the protein levels of ZnT3 and ZnT6 are markedly and significantly reduced in the spinal cords of ALS patients, while ZnT5 levels show a tendency to decrease, although not significantly. 571 Importantly, dysregulation of zinc has recently been identified to be a possible procedure causing the disequilibrium in the nucleocytoplasmic distribution of SFPQ in neurodegenerative disorders, consisting of both AD and ALS. 572 SFPQ, an omnipresent nuclear RNA-binding protein intricately involved in diverse facets of RNA genesis, has been closely associated with neuropathological disorders, including AD and ALS. 573 , 574

In conclusion, cellular zinc metabolism appears to play a crucial role in the pathogenesis of neurodegenerative diseases. Altered zinc homeostasis can lead to the formation of senile plaques in AD and contribute to α-synuclein aggregation in PD. ZD and dysregulation have been implicated in synaptic dysfunction and impaired learning and memory. Understanding the intricate relationship between zinc and neurodegenerative diseases may offer potential therapeutic strategies for managing these conditions.

Therapeutic targets for cellular zinc metabolism

In the realm of medical research, identifying and understanding therapeutic targets for cellular zinc metabolism has become an intriguing area of study. The delicate balance of zinc within cells is critical for maintaining various cellular processes and overall physiological well-being. In this essay, we delve into the significance of therapeutic targets related to cellular zinc metabolism, shedding light on their potential implications for human health and developing novel therapeutic interventions.

Zinc transporters

Therapeutic potential of zinc transporters in carcinogenesis.

Zinc transporters not only contribute significantly to the onset and progression of cancer, but they are also implicated in the development of both chemoresistance and radiotherapy resistance. This positions zinc transporters as potential targets for breakthroughs in cancer therapy. Current therapeutic strategies primarily focus on the ZIP family of transporters, employing a variety of approaches, including antibody-drug conjugates (ADCs), siRNAs, and natural inhibitors (Table 1 ). These therapies have demonstrated promising efficacy, and as a result, we posit that the targeting of zinc transporters may emerge as a focal point in the development of future anticancer drugs.

The development of chemoresistance often limits the success of anti-cancer treatments. The acquired resistance is driven to some extent by intra-tumor heterogeneity, mainly directed by cancer stem cells (CSCs). 575 Moreover, the difference between CSCs and non-CSCs within the tumor microenvironment may be primarily attributable to a cell biological procedure called EMT. 576 , 577 Activation of the EMT program enables tumor cells to resist the therapeutic agents, which is consistent with the attribute of CSCs. 578 , 579 As previously mentioned, zinc transporters are pivotal in cell stemness and EMT programs, reflecting their function in chemoresistance. For example, ZIP4 increases gemcitabine resistance primarily due to the activation of ZEB1, via p-STAT3 in PC cells. 395 In other words, ZIP4 upregulated the expression of ZEB1 in PC, which in turn induced a substantial downregulation of gemcitabine uptake protein ENT1 by integrin α3β1, ultimately limiting drug internalization through activation of the MAP kinase JNK. Besides, ZEB1 has also been proven to confer PC drug resistance by suppressing miR-20331. 401 Nabhan et al. found that gemcitabine activity requires caspase activation in multiple myeloma. 580 Interestingly, ZIP4 regulates PC cell apoptosis through the cleavage of caspase. 581 So far, gemcitabine-based therapies have remained the standard of practice for treating advanced PC. 582 Obviously, ZIP4 knockdown combined with gemcitabine may be another promising novel approach for the treatment of PC metastasis and drug resistance.

Moreover, another study substantiated that ZIP4 facilitates EMT of NSCLC. The mechanism is through activation of the Snail-N-cadherin pathway. 583 Similarly, siZIP4 evoked an epithelioid phenotype in NSCLC, reduced the expression of CSC markers, and elevated cisplatin sensitivity. 584 In contrast, within high-grade serous ovarian cancer (HGSOC), the overexpression of ZIP4 increased chemoresistance to cisplatin and doxorubicin. 585 Mechanistically, ZIP4 is an upstream regulator of NOTCH3, a storable signature of CSC in HGSOC. NOTCH3 can regulate proliferation, acid resistance, and drug resistance in carcinomas. 586 , 587 Currently, developing more efficient siRNA delivery techniques is an active segment of ovarian cancer research, 588 and targeting ZIP4 holds excellent promise. In a study on osteosarcoma, the authors found that ZIP10 expression is induced by chemotherapy and that subsequent increased intracellular zinc content activated CREB and promoted ITGA10 expression. 589 Notably, ITGA10 predicted poor osteosarcoma survival because it could promote chemoresistance through PI3K/AKT signaling. Strikingly, the CREB inhibitor 666-15 as well as another small molecule, the PI3K/AKT inhibitor GSK690693, attenuated chemoresistance in the cancer cells with ZIP10 overexpression.

In addition to mediating chemoresistance in tumor cells, zinc transporters also contributed to chemoresistance mediated in stroma cells. It has been reported that interstitial space connection between cancer cells and matrix cells might underpin tumor proliferation and chemoresistance. 590 , 591 In the tumor microenvironment of the lung cancer model, the ZIP1 + CAF subgroup is enrichment after chemotherapy and developed potent gapped junctions with tumor cells via up-regulation of the CX43 protein. 592 This study described a fascinating zinc recycling procedure. Chemotherapy induces necrosis in dying cancer cells and releases unstable zinc to the extracellular compartment. In chemotherapy, tumor cells are inhibited from taking up zinc from the extracellular space, which may lead to ZD in tumor cells. However, ZIP1 + fibroblasts have the ability to serve as zinc reservoirs, allowing the transfer of zinc from fibroblasts into tumor cells, and leading to the induction of ABCB1-mediated drug efflux and chemoresistance. In summary, zinc transporters exert an imperative effect in the tumor microenvironment, helping cancer cells to generate chemoresistance by regulating zinc concentration.

It is well-documented that radiotherapy induces cancer cell apoptosis by DNA damaging. Zinc is essential for the protection of cells against DNA damage, and its role appears to be enhanced in cancer cells. 593 , 594 ZD significantly influences cell cycle. 595 For example, in ESCC, miR-193b modulates the expression of ZIP5 and Cyclin D1. 596 In ZD, miR-193b was observed to be silenced by methylation, which increases ZIP5 expression. Subsequently, ZIP5 overexpression enhanced cellular zinc content, thereby diminishing the DNA damage from radiotherapy. 596 Additionally, radiotherapy resistance is a major barrier limiting the favorable prognosis in NPC as it may lead to tumor recurrence. 597 Zeng et al. found that raised ZIP4 expression activated the PI3K/AKT pathway to induce EMT in NPC cell line C666-1. 77 Accordingly, ZIP4 inhibition augmented radiation-induced apoptosis of C666-1 cells ex vivo and in vivo. Crucially, targeting ZIP4 in conjunction with radiotherapy may be an effective new therapy for treating NPC. 77

ADC is a novel anti-cancer drug consisting of a monoclonal antibody coupled with a cytotoxic drug via chemical linker. 598 ZIP6 is the cell surfacing target that is critical in cancer progression, which is undoubtedly the best candidate for ADC therapy. 599 , 600 As a result, inhibitors of ZIP6, a promising target, are being developed. For example, Seattle Genetics (SGN)-LIV1A or ladiratuzumab vedotin (LV), is currently in clinical trials for metastatic BC. 156 , 601 LIV-1, also called ZIP6, is a transmembrane protein overexpressing in BC. As an ADC, (SGN)-LIV1A is composed of an antibody that specifically binds to ZIP6 on BC cells and a potent cytotoxic drug payload. Upon binding to ZIP6-positive BC cells, (SGN)-LIV1A delivers the cytotoxic drug directly to the cancer cells, inducing cell death.

In addition to ADCs targeting ZIP6, a few small molecules have been reported. For instance, M9S1 extracted from Moringa oleifera significantly downregulated the expression of ZIP6 in MDA-MB-231 tumor, 602 treatment with STAT3 inhibitor peptide, cell-permeable (#573096, Sigma). Besides, the antiestrogens (Faslodex and 4‐hydroxytamoxifen, each 100 nM) also indicated that the expression of LIV-1 was decreased in MCF7 cells. 157 Through phenotypic screening of compounds, a ZIP7 inhibitor, NVS-ZP7-4, was identified that dominates the Notch signaling pathway in T-cell acute lymphoblastic leukemia (T-ALL) cell lines and initiates apoptosis by inducing ER stress. 603 Another research group found that the administration of CK2 inhibitors, such as DMAT (dimehtylamino-4,5,6,7-tetrabromo-1H-benzamidazole) or TBB (4,5,6,7-tetrabromobenzotriazole), inhibited the activity of ZIP7 and was well tolerated by cancer patients. 168 Another advantage of targeting ZIP7 in cancer is that it inhibits the mobilization of a large amount of tyrosine kinases, preventing cancer cells from shifting into another signaling pathway for regeneration. 148

Additionally, testosterone promotes melanoma proliferation through the activation of ZIP9. 461 The classic FDA-approved androgen receptor inhibitor bicalutamide also inhibits ZIP9, thus the antagonist of the tumor-promoting role of testosterone in melanoma, 461 suggesting that ZIP9 may be an effective target for melanoma and other cancers. Correspondingly, novel evidence shows that another androgen, dihydrotestosterone, can increase migration and invasion via ZIP9-mediated intracellular Gαi/MAPK/MMP9 signaling in bladder cancer. 604 Furthermore, bladder cancer progression dependent on ZIP9 could be inhibited by dutasteride, a 5α-reductase inhibitor. 605

Notably, the transcription factor STAT3 was strongly activated and related to a worse outcome in GC. 606 XYA-2, a novel STAT3 naturally occurring product inhibitor, has recently been identified. It synergistically suppresses the expression of MYC and ZIP10 (two downstream genes of STAT3), which exerts an anti-carcinogenic activity. 431 Furthermore, ZIP6/ZIP10 heteromer plays an essential role in zinc-induced mitosis, involving breast cancer proliferation. 156 , 334 Therefore, targeting the ZIP6/ZIP10 heteromer could be a significant approach to inhibit breast cancer invasion. Nimmanon et al. 156 utilized ZIP6 residues 240–253 (ZIP6-Y) and ZIP10 residues 46–59 (ZIP10B) to target ZIP6 and ZIP10, preventing their heteromer formation and thereby impeding the progression of mitosis.

Most tumor-targeted therapeutic studies on zinc transporters have primarily focused on ZIPs, while fewer investigations have been conducted on ZnTs. However, several tumor types, such as pancreatic cancer 607 and GC, 430 exhibit low expression levels of ZnTs. Targeting low-expressed genes is a viable strategy. Gene therapy techniques, 608 such as viral vectors or nanoparticle-based delivery systems, could be employed to deliver ZnTs specifically to tumor cells, enhancing the expression of these low-expressed transporters and providing a targeted therapeutic effect. Alternatively, nanoparticle-based delivery 609 of ZnT’s activators may offer a targeted therapeutic approach. By targeting low-expressed zinc transporter proteins, especially members of the ZnT family, a novel perspective emerges to dysregulate zinc homeostasis in cancer cells.

Thoughtfully, zinc plays an essential physiological function in cells, presenting a dual impact in tumor therapy. Targeting zinc or zinc transporters for tumor therapy shows promise, but potential toxic effects must be considered. Inhibiting zinc transporters or chelating zinc can disrupt vital processes for cancer cell survival and proliferation, displaying potential as an anticancer strategy. Obviously, the potential of targeting zinc transporters in cancer therapy has been identified, and the development of targeted small molecule drugs for clinical cancer patients is imminent. The small molecules potentially targeting the aberrantly activated zinc transporters have been summarized in Table 1 . However, zinc’s significance in normal cellular functions, including DNA repair 610 and immune responses, 611 warrants caution to minimize off-target toxic effects. Precise optimization of zinc-targeted therapies is necessary to achieve tumor-selective cytotoxicity without harming healthy tissues. Understanding zinc’s specific molecular mechanisms in tumorigenesis is pivotal for developing low-toxicity targeted therapies.

Targeting zinc transporters in other diseases

While much of the current research on zinc transporter targeting has been concentrated on tumoral diseases, these essential proteins are not limited to oncological applications. Emerging evidence reveals their significant potential as therapeutic targets for a spectrum of disorders, including anemia, diabetes, malignant muscular dystrophy, and liver fibrosis. Table 2 summarizes the clinical value of targeting zinc transporters beyond cancer therapy.

Emerging research involving two distinctive models, including zip10 mutant zebrafish as well as the hematopoietic Zip10-deficient mice, has made significant strides in our understanding of hematopoiesis. 50 Intriguingly, both models demonstrated more pronounced hematopoietic impairment than their counterparts lacking transferrin receptor 1, an established iron-gatekeeper. Research outcomes suggest a larger effect of zinc than iron in early hematopoietic stem cells (HSCs), underlining the significance of ZIP10 and zinc homeostasis in promoting proliferation and differentiation of fetal HSCs. Thus, a new vista opens for developing of therapeutic strategies against early fetal anemia by targeting ZIP10.

As mentioned in the previous section, zinc and its transporter proteins are implicated in insulin synthesis, secretion, and utilization. A particular study shed light on Zip5, which was found to be down-regulated in pancreatic β-cells of a diabetic mouse model. 612 Intriguingly, the study revealed that zinc influx via Zip5 induced Glut2 expression through the activation of Sirt1-mediated Pgc-1α, proposing Zip5 as potential therapeutic target for diabetes-related diseases. Additionally, zinc transporters, specifically ZIP14, seem to be potential game-changers in the treatment of malignant muscular dystrophy. A conspicuous upregulation of ZIP14 was observed in dystrophic muscles from metastatic cancer. Further investigation revealed that ZIP14-mediated zinc accumulations in differentiating muscle cells cause deletion of myosin heavy chain. 613 This finding underscores the importance of zinc homeostasis regulation in metastatic carcinoma-induced muscular dystrophy and suggests new avenues for treatment by targeting ZIP14.

In the context of liver health, zinc and its transport proteins carry immense importance, particularly in cases of liver fibrosis or cirrhosis. A model of iron metabolism disorders, the Trf-LKO mouse model, was subjected to hepatocyte-specific Trf knockout. 614 The absence of hepatic Zip14 expression reduced hepatic iron build-up, thereby alleviating iron-death-mediated hepatic fibrosis triggered by a high-iron diet or CCl4 injection. Notably, Zip14 can transport iron ions in addition to zinc ions, providing another potential therapeutic avenue for preventing iron-death-induced liver fibrosis. Above all, the diverse roles of zinc transporters underscore their potential as therapeutic targets. The continued exploration of these transporter proteins will likely yield more significant insights and open the door to a broader range of therapeutic applications.

Therapeutic potential of MTs

MTs, by virtue of their metal-binding capabilities, are central to many physiological and pathophysiological processes. They notably regulate zinc and copper homeostasis, shield against oxidative stress, and detoxify heavy metals. 615 , 616 , 617 The exploratory frontier of MTs as potential therapeutic agents has been pushed substantially in recent times.

Neurodegenerative disorders such as AD and PD often exhibit aberrant metal homeostasis and pronounced oxidative stress, paving the way for the potential therapeutic application of MTs. 618 , 619 , 620 Despite the seemingly promising outlook, some investigations have paradoxically led to contrary outcomes. For instance, the Tg2576 mouse model for AD, when subjected to an MT1/2-deficiency, demonstrated a partial rescuing of mortality and body weight changes that were induced by the human amyloid precursor protein. 621 In addition, a reduction in amyloid plaque burden has been observed across both the cerebral cortex and hippocampus, although the overall effects on amyloid cascade, neuroinflammation, and behavior are complicated because of the deletion of MT1/2. 622 In another study focusing on ocular neovascularization, a contributory factor to blindness, MT1/2 was found to play significant roles in retinal and choroidal neovascularization. The authors proposed the potential of MT1/2 as novel therapeutic targets for diseases involving ocular angiogenesis. 623

Furthermore, MTs have demonstrated potential applicability in cancer therapy. Abnormal MT expressions have been detected in numerous cancer types, often exhibiting a correlation between the level of MTs in tumor tissue and disease prognosis. In the context of CRC, MTs are commonly viewed as oncogenes. There is experimental evidence indicating SPINK1’s role in promoting tumor survival in CRC via the suppression of MTs. 624 However, contrary studies have emerged, showing DC-SIGNR’s ability to encourage cancer cell metastasis in CRC through the promotion of MTs. 625 These opposing findings underscore the intricate interplay between MTs and cellular mechanisms during cancer progression.

In conclusion, despite the clearly apparent therapeutic potential of MTs, their role is convoluted and context-dependent. To grasp fully the biological functions of MTs and to harness them effectively for therapeutic strategies, we require a profound understanding which can only come from further dedicated research.

Zinc-based therapeutics and measurement

Beyond targeting cellular zinc metabolism components, the development of zinc-based therapeutics itself is a burgeoning field. Utilizing zinc ions or zinc complexes as therapeutic agents holds potential in various medical applications, including wound healing, antimicrobial treatments, and zinc supplementation for zinc-deficiency-related conditions. The clinical applications of zinc supplements, zinc chelators have been summarized in Table 3 . Meanwhile, Table 4 summarizes the measurements of cellular free zinc.

Zinc supplements

Zinc’s significance in maintaining overall health is extensively discussed in our review. Correspondingly, ZD results in developmental retardation of children, delayed genital development and hypogonadism, skin disorders, hair loss, teratogenic effects, as well as weakened immune function, leading to an increased susceptibility to infections. 626 , 627 Given the wide range of essential biological functions zinc performs, addressing ZD through proper nutrition could make a huge contribution to various facets of human health.

The European Food Safety Authority has delineated different reference daily intakes of zinc for different population groups. 628 , 629 , 630 Specifically, these intake guidelines prescribe a range of 9.4–16.3 mg for men, 7.5–12.7 mg for women, 9.1–14.3 mg for pregnant women, and a lower limit of 5.5–7.4 mg for children aged between 4 and 10 years. Furthermore, they propose an upper threshold for zinc intake, at 25 mg/day for adults, and 7–10 mg/day for children aged between 4 and 13 years, to prevent potential zinc toxicity. Regarding supplements or food fortification, the European Union has authorized several zinc compounds. Among these, zinc sulfate and zinc oxide stand out as popular choices due to their cost-effectiveness. 631 , 632 Zinc sulfate, being water-soluble and comprising 23% zinc, and zinc oxide, though water-insoluble but containing a substantial 80% zinc, are extensively used. 632 Concurrently, zinc citrate has emerged as a promising alternative due to its sensory attributes. This compound contains up to 31% zinc, is minimally insoluble in water, has no odor, and is relatively cost-effective, making it an ideal choice for supplementation. 633 However, data regarding the absorption efficacy of these compounds in humans remains somewhat limited. Research in rats have shown that supplementation with zinc gluconate or zinc citrate resulted in a significant increase in zinc concentrations in the prostate, while zinc sulfate had no effect. 634 Thus, understanding zinc intake recommendations and the efficiency of different zinc compounds for supplementation is crucial to fully optimize the benefits of zinc for various demographic groups. As further research unfolds, it will be important to monitor these developments, to refine and update guidelines accordingly.

Diabetics lose zinc due to increased urinary excretion, leading to diabetic complications. Zinc was described as having insulin-mimetic effects, so zinc supplements may be appropriate for people with diabetes. 635 The ameliorative benefit of zinc supplements in diabetics can be summarized as the potential hypoglycemic effect of zinc, beneficial modulation of concomitant metabolic aberrations and impaired anti-oxidant status, and attenuation of renal lesions. 636 , 637 A meta-analysis showed that zinc supplements dramatically reduced glycemic indices, including two-hour postprandial glucose, fast blood sugar (FBS), and hemoglobin A1c, in all randomized controlled trials. 638 Zinc also has a favorable effect on blood lipids. 639 In addition, low-dose (<25 mg/day), and prolonged (≥12 weeks) intake of zinc from supplements with potential biofortification may be beneficial in reducing risk factors for T2D and cardiovascular disease. 640

In addition, under physiological conditions, zinc binds preferentially to MT, further activating MT to exert its anti-oxidative stress function. Studies have shown that zinc supplementation alleviates MT and oxidative stress in renal tissues of streptozotocin-induced diabetic rats, thereby preventing the development of diabetic nephropathy. 641 Another animal study has shown that zinc supplementation, in particular, reduces the probability of hyperglycemia-mediated renal injury, which also involves the process of oxidative stress. 642 Similarly, an animal study involving streptozotocin-induced diabetic rats has shown that zinc supplementation may protect against diabetes-induced peripheral nerve damage by stimulating MT synthesis and decreasing oxidative stress. 643

Beyond MTs, zinc supplementation also significantly affects the expression of zinc transporters in diabetic patients. 644 Interestingly, the mRNA expression of ZnT8, a transporter closely tied to insulin secretion and hence diabetic conditions, displayed considerable variability. Notably, higher levels of HbA1c, an indicator of long-term glucose control, were found in those participants who exhibited ZnT8 expression compared to their counterparts with no detectable ZnT8 expression. 644 Besides, a positive correlation between the mRNA of ZnT5 and ZIP3 was observed exclusively among participants receiving zinc supplementation. However, the same supplementation seemed to nullify the correlation between ZnT5 and ZIP10. In addition to basic supplementation, recent research has made strides in applying zinc-based therapies for diabetes management. For instance, novel zinc coordination compounds 645 and zinc oxide nanoparticles 646 have been explored for their potential to improve clinical outcomes in diabetes.

Diarrhea leads to significant zinc loss, and zinc supplements have proven effective in their treatment. 647 However, the exact mechanism underlying zinc’s therapeutic effects and its role in preventing subsequent morbidity remains unclear. This may be because zinc is indispensable in maintaining normal immune function. 648 The WHO recommends zinc supplementation alongside oral rehydration salts for diarrhea management. Despite its benefits, zinc supplementation may lead to some side effects. In studies, infants and children receiving zinc gluconate (10 mg or 20 mg of elemental zinc, respectively) experienced more days with vomiting compared to the control group. 649 Besides, one systematic review reported a higher risk of vomiting with zinc gluconate compared to zinc sulfate or zinc acetate. 650 It has been suggested that the unpleasant taste of zinc contributes to vomiting, but this is more probably because of zinc’s gastric irritant properties. 651

In fact, higher concentrations of zinc have been found to disrupt the absorption of other essential trace elements, especially copper. 652 Consequently, patients with copper overload, such as those with Wilson’s disease, may gain from treatment with 50 mg of zinc acetate three or more times a day, which remains highly effective for up to 10 years. 653 However, it is crucial to be cautious about potential adverse effects. One concern is that zinc supplementation could result in copper deficiency, in turn causing severe anemia and neutropenia. 654 Moreover, supplementation with 80 mg of zinc per day for a week resulted in the suppression of mixed lymphocyte cultures in the body, demonstrating that high levels of zinc can impede immune function. 655 Thus, to ensure the safe and effective use of zinc supplementation, it is recommended to limit the daily dose to no more than 25 mg. 640 Higher dosages, especially extreme dosages of more than 75 mg/day, may increase the risk of developing aggressive prostate cancer. 640 , 656 These findings are in line with the tolerable upper intake levels (ULs) of zinc set in both the Americans (40 mg/day) and Europeans (25 mg/day). 657

Zinc chelators

In laboratory settings, researchers utilize specific zinc chelators to investigate processes that rely on zinc. One of the most used selective and membrane-permeable chelators for zinc ions is N, N, N’, N’-tetrakis (2-pyridinylmethyl)-1,2-ethanediamine (TPEN). TPEN exhibits the highest affinity for zinc compared to other chelators (Ka = 1015.58 M −1 ). 44 Numerous reports have shown that depletion of zinc from cells through chelation is considered a potential cancer treatment strategy. 160 , 658 , 659 However, it is essential to interpret zinc effects cautiously and assess their physiological relevance in such studies. TPEN’s strong zinc-binding affinity enables it to virtually eliminate the entire zinc response pool, a condition not attainable under normal or pathological circumstances, leading to predictable cell death.

In contrast, 2,3-dimercapto-1-propanesulfonic acid (DMPS), a heavy metal chelator, has the highest affinity for copper. 660 Interestingly, DMPS has also been identified as a zinc chelator and has been found to effectively antagonize Zn 2+ -dependent snake venom metalloproteinases in vitro. 661 Another widely used chelating agent is EDTA (Ethylenediaminetetraacetic acid), which forms stable complexes with various metal ions, including zinc. 662 For example, in the context of therapeutic modulation in traumatic brain injury (TBI), zinc has emerged as a target. 663 EDTA significantly increased the expression of neuroprotective genes and proteins after TBI.

Clioquinol, recently used as a topical agent for treating some skin infections, has drawn interest from researchers due to its zinc and copper chelating properties, making it a potential candidate for AD. 664 , 665 The chelating activity of zinc appears to play a direct role in heme production. 666 Both zinc and copper contribute to the deposition and stabilization of amyloid plaques, and chelators were shown to solubilize amyloid deposits. 667 Notably, as zinc is essential for heme synthesis, which is recognized as increased in the brain of AD sufferers leading to oxidative stress, clioquinol’s binding to zinc reduces heme synthesis and oxidative stress.

Zinc measurement

The complexity of distinguishing protein-bound zinc from unbound zinc in experimental setups has led to the development and employment of various methods for specific investigations. The techniques used can be broadly divided into two categories: analytical methods and fluorescence techniques.

Analytical methods such as atomic absorption/emission spectroscopy and inductively coupled plasma mass spectrometry offer a relatively straightforward means of measuring total zinc, including both bound and unbound forms. 668 These methods are particularly useful in obtaining a holistic view of zinc content within a given sample.

Moreover, fluorescence microscopy/spectroscopy is primarily employed to study the zinc pool without binding to protein. Two main fluorescence techniques are key in this aspect: low molecular weight (LMW) fluorescent/fluorogenic chelating agents (probes) and genetically encoded fluorescent proteins. 12 Typically bifunctional and comprising both chelating agent and fluorophore, LMW probes function mainly on the principle of photo-induced electron transfer (PET). 669 PET occurs among fluorophore and the chelating component, leading to fluorescence quenching, and this process is disrupted by zinc binding, leading to enhanced emission. 670

Further advancements in fluorescence techniques have led to the common utilization of Förster Resonance Energy Transfer (FRET) and Bioluminescence Resonance Energy Transfer (BRET) sensors, both genetically encoded specifically for zinc. 671 FRET sensors, with their inherently ratiometric nature, utilize interconnected donor as well as acceptor molecules, linked by a peptide sequence containing a zinc-binding domain. 669 Changes in zinc concentration lead to conformational changes that alter energy transmission and affect the strength of the emission fluorescence. 669 , 672 BRET, conversely, focuses on the transmission of energy across the fluorescent structural domains of the donor luciferase and the acceptor. Major advantages offered by BRET sensors are their resistance to photobleaching, absence of phototoxicity, and lack of background autofluorescence during measurement. 671 , 673 These characteristics make BRET an invaluable tool for examining dynamic interactions and enzymatic activity in living cells.

Besides, specific genetically encoded sensors like CALWY, Zap/ZifCY, and those based on carbonic anhydrase are increasingly being used to gain enhanced control over intracellular zinc concentration and location. 674 , 675 , 676 , 677 , 678 These sensors provide tailored advantages in managing intracellular variables, including concentration, localization, and calibration. Recently, a set of innovative organelle-targetable zinc fluorescent probes has been developed, comprising ZnDA-1H, ZnDA2H, and ZnDA-3H. 27 These cutting-edge probes feature HaloTag ligand (HTL) molecules, which facilitate precise localization within specific organelles, and provide an excellent means of studying the physiological functions of the ZIP members residing in the ER and Golgi apparatus.

In conclusion, from comprehensive analytical methods to fine-tuned fluorescence techniques like FRET and BRET, researchers are now equipped with diverse tools that provide multidimensional perspectives on zinc’s behavior and interactions. The synthesis of these tools within a clinical context could revolutionize patient care, fostering a new era of precision medicine where zinc measurement and manipulation become critical components in disease prevention, diagnosis, and treatment.

Conclusion and future direction

Undoubtedly, cellular zinc metabolism and zinc signaling are critical in a variety of biological functions, spanning from essential cellular processes to the development and progression of various diseases. Zinc acts as an essential modulator of cell homeostasis as well as is engaged in key signaling pathways that impact cell growth, proliferation, immune responses, and DNA repair. Dysregulation of zinc metabolism and signaling has been linked to numerous diseases, including cancer, neurodegenerative disorders, and infectious diseases.

Evidence suggests that a safe range of zinc intake is negatively associated with cancer risk. However, cancer cells inevitably require more zinc to maintain the oncogenic properties and metastasis, which functionally relies on the zinc transporter. Previous studies reported that the zinc transporter is aberrantly elevated and activated among multiple tumor types, particularly GI cancers. The significant upregulation of zinc transporters in GI cancers might be because that zinc absorption depends on the epithelial cells of the GI tract, which is the most vulnerable region for zinc homeostasis disorders. In BC and ESCC, zinc transporter ZIP6 is regarded as a diagnostic and prognostic biomarker. Similarly, ZIP10 is regarded as a cancer marker based on its methylation in CRC. Aberrant expression or hyperactivation of zinc transporters would also contribute to tumor resistance, which could be a malprognostic factor for cancer patients. Therefore, aiming at zinc transporters is expected to improve the efficacy of tumor therapies. Meanwhile, since zinc transporter proteins are predominantly distributed on cell membranes, developing small molecules or monoclonal antibodies for specific targeting is feasible.

Obviously, targeting zinc transporters offers potential strategies for treating various diseases, including cancer, neurodegenerative disorders, and infections. However, the study of zinc transporters is still at an infant stage. There are still several issues to be addressed, especially in cancer research. Firstly, the molecular mechanism for the expression of zinc transporters should be further elucidated. Nearly all the upstream regulatory mechanisms of the zinc transporter are still lacking. Thus, it is imperative to elucidate the critical transcriptional factors in regulating zinc transporter expression. Meanwhile, post-transcriptional and post-transcriptional regulation mechanisms need to be addressed. Next, several intellectual gaps still exist concerning the clinical relevance of zinc transporters and their downstream effectors in tumorigenesis. As the mechanisms of ZIPs and ZnTs are totally different in different cancer types, the detailed functional roles and underlying mechanisms are required to be comprehensively revealed. A comprehensive study of zinc transporter-related signaling might accelerate the development of combination therapeutic approaches specifically geared toward zinc transporters. Furthermore, apart from the cancer cell itself, the gut microbiota, including bacteria and viruses, has been implicated in playing a vital role in tumorigenesis and impacting the therapeutic efficacies of cancer patients, especially GI patients. We speculated that the gut microbiome might manipulate the zinc transporter expression and is involved in zinc-related signaling transduction. It will be a research focus on how the microbiome changes reshape the zinc transporters in tumor initiation and development. Finally, targeting zinc transporter is promising for eliminating cancer by developing small-molecule drugs and monoclonal antibodies. Notably, taking advantage of the fact that most zinc transporters are found to be localized on the membrane surface of cancer cells, targeting cancer cells with ADCs is also a potential therapeutic strategy. Meanwhile, it is required to carefully appraise the benefits and side effects of drugs targeting zinc transporters and develop novel delivery strategies. In conclusion, zinc transporters play multifaceted roles in solid tumors, and serve as diagnostic/prognostic tools and therapeutic targets.

Undeniably, the understanding of cellular zinc metabolism and zinc signaling is still evolving, and future investigations in this field are promising. The potential of zinc-based therapies, such as zinc supplements and zinc chelators, warrants exploration in the context of specific diseases. Understanding the optimal dosage, timing, and potential side effects of zinc supplementation or chelation will be crucial for the successful translation of these approaches into clinical practice. Besides, the detection of zinc levels and zinc-related molecular alterations in biological samples may serve as diagnostic biomarkers for various diseases, aiding early detection and guiding treatment decisions. In conclusion, research efforts in cellular zinc metabolism and zinc signaling will deepen the scope of our comprehension of fundamental biological processes and pioneer the way for emerging therapies to combat disease.

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Acknowledgements

This study was supported by National Natural Science Foundation of China (NSFC) (2022, No. 82272990), Health and Medical Research Fund (HMRF, 08190586), CUHK direct grant (2022.001 and 2020.004), and Cheng Yue Pui Charity Foundation. We acknowledge the TCGA Research Network ( http://cancergenome.nih.gov/ ) and the cBioPortal for Cancer Genomics ( https://www.cbioportal.org/ ) for providing the datasets and analysis. Part of the images was generated by BioRender ( https://biorender.com/ ) and GEPIA2 ( http://gepia2.cancer-pku.cn/#isoform ). We also appreciate the technical support from Core Utilities of Cancer Genomics and Pathobiology of the Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong.

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These authors contributed equally: Bonan Chen, Peiyao Yu

Authors and Affiliations

Department of Anatomical and Cellular Pathology, State Key Laboratory of Translational Oncology, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, China

Bonan Chen, Wai Nok Chan, Fuda Xie, Kwok Wai Lo, Gary M. K. Tse, Wei Kang & Ka Fai To

State Key Laboratory of Digestive Disease, Institute of Digestive Disease, The Chinese University of Hong Kong, Hong Kong, China

Bonan Chen, Wai Nok Chan, Fuda Xie, Jun Yu, Wei Kang & Ka Fai To

CUHK-Shenzhen Research Institute, The Chinese University of Hong Kong, Shenzhen, China

Bonan Chen, Wai Nok Chan, Fuda Xie & Wei Kang

Department of Pathology, Nanfang Hospital and Basic Medical College, Southern Medical University, Guangdong Province Key Laboratory of Molecular Tumor Pathology, Guangzhou, China

Peiyao Yu & Li Liang

Institute of Biomedical Research, Taihe Hospital, Hubei University of Medicine, Shiyan, China

Yigan Zhang

Department of Pediatrics, The Chinese University of Hong Kong, Hong Kong, China

Kam Tong Leung

Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong, China

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K.F.T. and W.K. offered directions on this manuscript. B.C., P.Y. drafted the manuscript together. B.C., W.N.C. and P.Y. made the figures and table. B.C., F.X. and Y.Z. reviewed the literature. L.L., K.T.L., K.W.L., J.Y. G.M.K.T. and W.K. reviewed the manuscript and gave comments. All authors have read and agreed to the published version of the manuscript.

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Correspondence to Wei Kang or Ka Fai To .

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Chen, B., Yu, P., Chan, W.N. et al. Cellular zinc metabolism and zinc signaling: from biological functions to diseases and therapeutic targets. Sig Transduct Target Ther 9 , 6 (2024). https://doi.org/10.1038/s41392-023-01679-y

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DOI : https://doi.org/10.1038/s41392-023-01679-y

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Zinc. By: Bo Jun Kim G9 Amber. About Zinc.

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Zinc By: Bo Jun Kim G9 Amber

About Zinc • Zinc, in commerce also spelter, is a metallic chemical element; it has the symbol Zn and atomic number 30. It is the first element of group 12 of the periodic table. Zinc is, in some respects, chemically similar to magnesium, because its ion is of similar size and its only common oxidation state is +2. Zinc is the 24th most abundant element in the Earth's crust and has five stable isotopes.

Discovery • German scientist Andreas Margraf discovered the element in 1746. Even if Margraf was recognized for the discovery of the element, many historians agree that the element was already used by ancient people. One of the evidences that the element was used in early societies is the prehistoric statuette that was recovered in Transylvania, which was made from 87.5 per cent zinc.

Major Producers • Zinc is the fourth-most common metal in use with an annual production of about 12 million tones. The world consumption of zinc is around 10774000 tons. China, United States, and Japan are the largest consumers of zinc. Among this countries, China is the largest zinc producer in the world.

Physical Properties • The physical properties of zinc include a blueish-white lustrous material. The material is brittle at ambient temps but malleable at 100- 150 degrees Celsius. Zinc is a metal that has a hexagonal crystal structure, a melting point of 419.58 degrees celcius and a boiling point of 907 degrees celcius

Application • World-wide use of zinc oxide is in excess of 1.2 million tones annually. On a contained zinc basis the oxide accounts for about 9% of metallic zinc. Probably 60% of zinc oxide uses secondary zinc, primarily top dross from continuous galvanising, as the zinc source. China is by far the dominant supplier and also largest user, followed by the U.S.. Although rubber products and in particular tires are the major use for rubber, there are considerable variations around the world in use patterns.

Health Issues • Advantages: Zinc sulfate is a very effective method for treating zinc deficiency, causing a person's zinc level to rise significantly when taken as a supplement. Almost all fertilizers use zinc sulfate because of its positive benefit to plants. Both over-the-counter and prescription acne medicines contain zinc sulfate, as well as other skin care products, because of its ability to kill microorganisms on the skin. • Disadvantages: It's likely that most women get enough zinc in their diets. Therefore, Adding a zinc supplement to your diet, however, can be dangerous to your health, causing stomach upset, nausea, vomiting, headache and anemia.

Biblography • http://www.ask.com/question/physical-properties-of-zinc • http://www.mapsofworld.com/minerals/world-zinc-producers.html • http://ezinearticles.com/?The-Discovery-of-Zinc&id=4http://wiki.answers.com/Q/What_are_the_physical_property_of_zinc?#slide=1305623 • http://woman.thenest.com/zinc-benefits-disadvantages-2046.html

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