From Fenton reaction to ferroptosis: chemistry of metal complexes in regulated cell death by lipid peroxidation.

作者：S. Shivangi, Bidare N. Sharathbabu, G. Mugesh · 发表于：Chemical Society Reviews · 年份：2026 · DOI：10.1039/d6cs00041j · 研究领域：Medicine

Ferroptosis is a regulated, iron-dependent form of cell death characterized by the unchecked peroxidation of polyunsaturated phospholipids and the collapse of cellular antioxidant defenses. Its therapeutic modulation has emerged as a promising strategy across a broad spectrum of diseases, particularly cancer, where ferroptosis induction offers opportunities to overcome apoptosis resistance and treatment tolerance. In this context, coordination chemistry provides a uniquely versatile platform for controlling intracellular redox processes, metal homeostasis, and radical reactivity, enabling the rational design of metal-based ferroptosis modulators. This review critically examines the rapidly expanding landscape of ferroptosis-inducing metal complexes derived from Fe, Cu, Mn, Co, Zn, Ga, Ru, Ir, Os, Pt, Au, and related elements for anticancer applications. We discuss how metal identity, oxidation state, coordination environment, and ligand architecture collectively govern redox reactivity, subcellular localization, biomolecular interactions, and catalytic reactive oxygen species generation. Particular emphasis is placed on the molecular mechanisms through which metallodrugs promote ferroptosis, including expansion of the labile iron pool (LIP), disruption of antioxidant defense pathways such as GPX4/GSH, ferroptosis suppressor protein 1 (FSP1)/coenzyme Q10 (CoQ10), and dihydroorotate dehydrogenase (DHODH), as well as initiation of lipid peroxidation through both non-enzymatic an...