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

Abstract

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 and enzyme-mediated processes. We further highlight the central role of ligand design in dictating ferroptotic activity. Soft sulfur-donor frameworks, including thiosemicarbazones and dithiocarbamates, facilitate Fe- and Cu-mediated redox cycling, whereas polypyridyl and macrocyclic scaffolds modulate metal-centered redox accessibility, kinetic stability, and intracellular trafficking. N-Heterocyclic carbene ligands provide an additional level of control by tuning metal-ligand electronic properties and exploiting the pronounced thiophilicity of Au(I) toward seleno- and thiol-containing proteins. Emerging strategies, including ionophore-based approaches, Trojan-horse iron-delivery approaches, and activatable metalloprodrug-based approaches, are also discussed as promising avenues for enhancing ferroptotic selectivity and efficacy. Finally, we outline key challenges that must be addressed to translate ferroptosis-inducing metallodrugs toward clinical application, including improving tumour selectivity, optimizing pharmacokinetic behaviour, understanding metal-specific toxicities, and establishing robust mechanistic biomarkers. Collectively, this review highlights how coordination chemistry can be leveraged to chemically programme ferroptotic susceptibility and positions metallodrug design as a powerful frontier in precision oncology.