Metal‐dependent regulated cell death: Molecular architecture and translational frontiers

作者：Haoliang Hu, Zhe Chen, Yaqi Li, Jiayi Peng, Jiangang Cao, Hong Zhou, Mengqi Wang, Yuejia Du, Hailin Wu, Huiqin Zhao, Shifang Huang, Dianmei Yu, Meiqing Liu, O. Shevchenko, N. Matveeva, Yiyuan Yang, Ke-Rui Huang, Deguan Lv, Junxia Min, Linxi Chen, Fudi Wang · 发表于：iMeta · 年份：2026 · DOI：10.1002/imt2.70141 · 研究领域：Medicine

Abstract Intracellular metal dyshomeostasis has emerged as a key regulator of specialized regulated cell death (RCD) programs, challenging classical views that regard necrosis as entirely accidental. This review systematically delineates the molecular architecture and translational trajectories underlying metal‐dependent RCD, including iron‐driven ferroptosis, copper‐mediated 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‐targeted proteotoxic stress to organelle‐specific bioenergetic failure, which arise following disruption of compartmentalized metal‐buffering 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‐resistant 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‐target multiorgan toxicity and complex in vivo crosstalk among interconnected death pathways (e.g., disulfidptosis and PANoptosis) represent major translational challenges, we...