{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nMT3 is a brain‐enriched metallothionein with unique structural and metal‐binding properties that distinguish it from the more ubiquitous MT1/MT2 isoforms. In neurons and brain endothelial cells, MT3 helps maintain metal homeostasis by binding zinc and copper, and under oxidative stress it can release zinc—thereby influencing lysosomal membrane integrity, autophagic flux, and the redox state. Its action triggers antioxidant defense pathways (for example, via PI3K/ERK‐mediated activation of Nrf2 and consequent HO‐1 upregulation) and counteracts the neurotoxicity of aberrant copper–amyloid interactions, suggesting a neuroprotective role in conditions such as ischemia, trauma, and Alzheimer’s disease."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "11"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn addition to its neuroprotective functions, MT3 plays diverse roles in tumorigenesis and cancer progression. In various epithelial malignancies—including prostate, gastric, esophageal, lung, adrenal, and bladder cancers—the expression of MT3 is often abnormal, as it can be either downregulated through hypermethylation or overexpressed in a context‐dependent manner. Functional studies have demonstrated that MT3 influences cell proliferation, apoptosis, invasion, and chemoresistance; for example, its up‐regulation may suppress tumor cell growth by inhibiting cell cycle progression and inducing apoptosis, while in other contexts MT3 enhances invasiveness via modulating matrix metalloproteases and downregulating tumor suppressors. These observations indicate that MT3’s impact on cancer may be multifaceted and highly dependent on cellular context."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "12", "end_ref": "29"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nMechanistic and structural studies have further illuminated how the unique domain organization of MT3 underpins its biological functions. Detailed analyses reveal that specific sequence motifs—such as an acidic hexapeptide insert and conserved cysteine‐rich clusters—govern its metal‐thiolate cluster stability, conformational dynamics, and reactivity. These features not only regulate its zinc/copper exchange and intracellular availability but also determine its responsiveness to stressors such as hypoxia (via HIF‐1–dependent pathways) and influence its interactions with other cellular proteins. Moreover, biophysical investigations demonstrate that the compact conformations of apo‐MT3 are sensitive to environmental conditions, thereby modulating its role in diverse tissues such as kidney proximal tubules and adrenal cortex, and contributing to its involvement in chemoresistance."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "30", "end_ref": "36"}]}, {"type": "t", "text": ""}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Ho Jin You, Kyung Jin Lee, Hye Gwang Jeong "}, {"type": "b", "children": [{"type": "t", "text": "Overexpression of human metallothionein-III prevents hydrogen peroxide-induced oxidative stress in human fibroblasts."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "FEBS Lett (2002)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/s0014-5793(02)02870-3"}], "href": "https://doi.org/10.1016/s0014-5793(02"}, {"type": "t", "text": "02870-3) PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12067712"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12067712"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Zhi-Chun Ding, Xin-Chen Teng, Bin Cai, et al. 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