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This review systematically delineates the molecular architecture and translational trajectories underlying metal\u2010dependent RCD, including iron\u2010driven ferroptosis, copper\u2010mediated cuproptosis, and additional emerging modalities such as calcicoptosis, necrosis by sodium overload (NECSO), and the newly designated zincoptosis, mnoptosis, and coptosis. We examined distinct execution mechanisms, ranging from membrane lipid peroxidation and lipoylation\u2010targeted proteotoxic stress to organelle\u2010specific bioenergetic failure, which arise following disruption of compartmentalized metal\u2010buffering networks. To bridge the persistent knowledge gap between foundational metallobiology and clinical application, we evaluated a bidirectional therapeutic framework: exploiting synthetic lethality and metabolic gating via clinical inducers (e.g., sorafenib, elesclomol) to selectively eliminate therapy\u2010resistant malignancies while deploying targeted pathway inhibitors and systemic agonists (e.g., dipyridamole, omaveloxolone) to limit pathological tissue degeneration in ischemic and neurodegenerative disorders. Recognizing that off\u2010target multiorgan toxicity and complex in vivo crosstalk among interconnected death pathways (e.g., disulfidptosis and PANoptosis) represent major translational challenges, we assessed advanced materials\u2010science strategies designed to overcome these barriers. Specifically, we highlighted the integration of single\u2010atom catalysts, stimuli\u2010responsive nanomedicines, and biomimetic carriers engineered to spatiotemporally confine catalytic oxidative flux. Finally, we examined the systemic immunological consequences of targeted metal dysregulation, detailing how metal\u2010induced immunogenic cell death and cyclic GMP\u2010AMP synthase (cGAS)\u2010stimulator of interferon genes (STING) pathway hyperactivation reshape immunosuppressive microenvironments and modulate sterile inflammation, thereby enhancing responsiveness to immune checkpoint blockade, providing a definitive molecular blueprint for next\u2010generation precision therapeutics.<\/jats:p>","DOI":"10.1002\/imt2.70141","type":"journal-article","created":{"date-parts":[[2026,7,7]],"date-time":"2026-07-07T03:05:29Z","timestamp":1783393529000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Metal\u2010dependent regulated cell death: Molecular architecture and translational 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