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

), 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.