Zinc-Mediated Defenses Against Toxic Heavy Metals and Metalloids: Mechanisms, Immunomodulation, and Therapeutic Relevance
Abstract
1. Introduction
2. Suppressive Effects of Heavy Metals on the Immune System
3. Importance of Zinc in Biological Functions
4. Zinc Deficiency and Its Adverse Effects: Significance of Zinc Supplementation in Human Health
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- Enhancing immune function to combat infections and diseases effectively, and thereby reducing respiratory tract infections (RTIs); cold, flu, sinusitis, pneumonia, and COVID-19.
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4.1. Zinc Supplementation in Cardiovascular Diseases
4.2. Zinc Supplementation in Neurodegenerative Disorders and Aging Process
5. Role of Zinc, Zinc Importers, and Transporters in the Immune System and Associated Disorders
6. Dysregulation of ZIP Transporters in Cancer
6.1. Role of ZIP1 in Prostate Cancer Development
6.2. Role of ZIP6, ZIP7, and ZIP10 in Breast Cancer Development
6.3. Role of ZIP4 in Pancreatic Cancer Development
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- Excess Zn accumulation mediated by ZIP4 overexpression may also affect the tumor microenvironment, consequently leading to induced inflammation and suppressed immunity, and finally, facilitating a conducive milieu for substantial cancer cell proliferation.
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- The ZIP4-mediated Zn influx activates ZF-transcription factors, facilitating the release of cancer-associated mutant genes from extracellular vesicles (EVs) through Ras-related protein Rab-27B (RAB27B)-mediated activation. Additionally, ZIP4 inhibits tight junction proteins such as zona occludens-1 (ZO-1) and claudin-1 via ZF E-box binding homeobox 1 (ZEB1), leading to increased tumor cell movement and motility through EMT (Figure 5C) [124,125].
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- Targeting ZIP4 expression or its downstream signaling pathways presents a promising strategy for developing novel therapeutic interventions for pancreatic cancer. By disrupting Zn dysregulation mediated by ZIP4 overexpression, it may be possible to impede cancer progression and improve patient outcomes [126].
ZIP Transporters (Importers) | Tissue Specificity | Functions | Mutation or Deficiency | Disorders | Ref |
---|---|---|---|---|---|
ZIP1 | Adults and fetal tissues | Rapid uptake and accumulation of Zn in prostate cells | Single or double ablation of ZIP1 | Prostate cancer; Abnormal embryonic development | [118] |
ZIP2 | Prostate and uterine epithelial cells | Uptake of Zn; Contact inhibition of normal epithelial cells | Single or double ablation of ZIP2 | Abnormal embryonic development; Tumor genesis | [119] |
ZIP3 | Bone marrow, spleen, small intestine, and liver | Responsible for Zn influx transporter | Single or double ablation of ZIP3 | Abnormal embryonic development | [122] |
ZIP4 | Kidney, small intestine, stomach, colon, jejunum and duodenum | Regulates Zn homeostasis | Loss of function and targeted disruption of the ZIP4 genes | AE, TEWL, IgE, and Th1/Th2 balance | [124] |
ZIP5 | Intestine, pancreas, liver, and kidney cells | Dietary uptake and homeostasis of Zn | Loss-of-function of ZIP5 gene | adHM | [125] |
ZIP6 | Prostate, placenta, and mammary glands | Act as a metalloproteinase | Loss-of-function of ZIP6 gene | Placenta cancer and metastasis | [121] |
ZIP7 | Mammary gland cells | Helps in Zn uptake | Loss-of-function of ZIP7 gene | Breast Cancer | [127] |
ZIP8 | Fibroblasts and chondrocytes | Causes Cd transport and toxicity in fibroblasts and chondrocytes | Hypomorphic mutation of ZIP8,Zn influx into cartilage chondrocytes lead to MMPs, Non-synonymous variant in ZIP8 | Organ morphogenesis and hematopoiesis; Osteoarthritis due to IL-1β, IL-8 and TNF-α; MMPs and ROS; TH1 cytokines (IFN-γ, IL-2), and Schizophrenia | [128] |
ZIP9 | Human lymphocytes | Activation of AKT in response to BCR activation | Lack of ZIP9 | Fecundity; Egg viability; Retardations in the offspring growth | [129] |
ZIP10 | Mammary glands | Aid in the Zn influx | Lack of ZIP10 | Impaired B-cell development; HIR | [121] |
ZIP11 | Testes, stomach, ileum, and cecum | For Zn transport | Lack of ZIP11 | Zn deficiency | [129] |
ZIP12 | Brain and eye | For cellular Zn uptake | Targeted ZIP12 disruption | PH in hypoxic conditions; Possible schizophrenia | [121] |
ZIP13 | Bone, teeth, and connective tissue | Maturation: osteoblasts/chondrocytes/fibroblasts | ZIP13 deficiency | EDS; SCD-EDS | [129] |
ZIP14 | Mammalian cells | Cd transport and toxicity | ZIP14-deficiency homozygous loss-of-function mutations | Growth, bone metabolism, and gluconeogenesis; Dystonia-parkinsonism; Neurodegeneration with hypermanganesemia in childhood. | [129] |
ZnT Transporters (Exporters) | Tissue Specificity | Functions | Mutations | Disorders | Ref |
---|---|---|---|---|---|
ZnT1 | Expressed in all tissues | Exporting metals from cytoplasm to extracellular medium | Targeted disruption of ZnT1 | Embryonic lethality and abnormal vulva formation | [68] |
ZnT2 | Mammary gland, prostate, retina, pancreas, small intestine, and kidney | Accumulation of metals in organelles | Targeted disruption or mutation of ZnT2 | Extremely low Zn content of breast milk | [70] |
ZnT3 | Brain, testes, and pancreas | Promotes the absorption of metal ions | Targeted ZnT3 disruption | Memory deficits with AD due to failure of Zn homeostasis proteins in neurons (MTIII- ZnT1-3) | [79] |
ZnT4 | Expressed in all cells | Loss-of-function mutation in ZnT4 (lethal milk mutant) | Post-natal lethality | [80] | |
ZnT5 and ZnT6 | PM/Golgi/vesicular membranes | Accumulation of metals in vesicles for transportation | ZnT5 and 6 -deficiency | Severe osteopenia with impaired DTH | [82] |
ZnT7 | PM/Golgi/vesicular membranes | Accumulation of metals in vesicles, for transportation | ZnT7-deficiency | HFD-IGT | [86] |
ZnT8 | Pancreatic β cells | Maintain the concentration of blood glucose | ZnT8-deficiency | Impaired insulin secretion and crystal formation in DM | [87] |
ZnT10 | PM/Golgi/vesicular membranes | Accumulation of metals in vesicles, for transportation | ZnT10 mutation | Dystonia-parkinsonism with hyper manganesemia, polycythemia, and CLD | [87] |
Type of Caner | Serum Zn Levels | Tissue Zn Levels | Abnormal Transporters | Ref |
---|---|---|---|---|
Breast | ZIP6 (), ZIP7 (), ZIP9 (), ZIP10 (), ZnT2 () | [70,121,129] | ||
Lung (NSCLC) | ZIP4 () | [124] | ||
Nasopharynx (NPC) | ZIP4 () | [124] | ||
ESCC | ZIP5 (), ZIP6 () | [121,125] | ||
Ovarian cancer | ZIP4 () | [124] | ||
Cervical cancer | Uncertain | ZIP7 () | [121] | |
Prostate cancer | ZIP1 , ZIP2 , ZIP3 , ZIP4 , ZIP9 (), ZnT4 | [80,118,119,122,124,129] |
7. Molecular Mechanisms, In Vitro, and In Vivo Studies
8. Conclusions and Future Perspectives
Author Contributions
Funding
Data Availability Statement
Conflicts of Interest
Abbreviations
ZFP | Zinc Finger Proteins |
ZIP | Zrt- and Irt-like protein |
ZnT | Zinc Transporter |
ZEB1 | Zinc finger E-box binding homeobox 1 |
MT | Metallothionein |
ECM | Extracellular matrix |
NK cells | Natural killer cells |
TNF | Tumor Necrosis Factor |
GPx | Glutathione peroxidase |
ILs | Interleukins |
IFNs | Interferons |
NOX | NADPH Oxidase |
PARP | Poly ADP-ribose polymerase |
ROS | Reactive oxygen species |
RREB1 | Ras-responsive element binding protein 1 |
RAB27B | Ras-related protein Rab-27B |
Aco2 | Mitochondrial aconitase |
SOD | Superoxide Dismutase |
MMPs | Matrix metalloproteinases |
AMPs | Antimicrobial peptides |
ATP | Adenosine triphosphate |
NAD | Nicotinamide Adenine Dinucleotide |
E-cad | Epithelial cadherin |
GSK-3β | Glycogen Synthase Kinase-3 beta |
STAT3 | Signal Transducer and Activator of Transcription 3 |
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Sangubotla, R.; Syed, S.; Mastan, A.; Lakshmi, B.A.; Kim, J. Zinc-Mediated Defenses Against Toxic Heavy Metals and Metalloids: Mechanisms, Immunomodulation, and Therapeutic Relevance. Int. J. Mol. Sci. 2025, 26, 9797. https://doi.org/10.3390/ijms26199797
Sangubotla R, Syed S, Mastan A, Lakshmi BA, Kim J. Zinc-Mediated Defenses Against Toxic Heavy Metals and Metalloids: Mechanisms, Immunomodulation, and Therapeutic Relevance. International Journal of Molecular Sciences. 2025; 26(19):9797. https://doi.org/10.3390/ijms26199797
Chicago/Turabian StyleSangubotla, Roopkumar, Shameer Syed, Anthati Mastan, Buddolla Anantha Lakshmi, and Jongsung Kim. 2025. "Zinc-Mediated Defenses Against Toxic Heavy Metals and Metalloids: Mechanisms, Immunomodulation, and Therapeutic Relevance" International Journal of Molecular Sciences 26, no. 19: 9797. https://doi.org/10.3390/ijms26199797
APA StyleSangubotla, R., Syed, S., Mastan, A., Lakshmi, B. A., & Kim, J. (2025). Zinc-Mediated Defenses Against Toxic Heavy Metals and Metalloids: Mechanisms, Immunomodulation, and Therapeutic Relevance. International Journal of Molecular Sciences, 26(19), 9797. https://doi.org/10.3390/ijms26199797