Ferroptosis: Core Mechanisms and Metabolic Regulation

This entry summarizes the molecular basis of ferroptosis, its metabolic and signalling regulation, its roles in major disease groups, and the principal therapeutic strategies targeting this cell-death pathway. Ferroptosis is an iron-dependent form of regulated cell death driven by uncontrolled peroxidation of polyunsaturated fatty acid-containing phospholipids. It is morphologically and biochemically distinct from apoptosis, necroptosis, autophagy, and pyroptosis and is characterized by iron accumulation, glutathione depletion, glutathione peroxidase 4 (GPX4) inactivation, and lipid peroxide accumulation. The core execution machinery involves labile iron, PUFA-phospholipid remodelling by ACSL4 and LPCAT3, lipoxygenase- and oxidoreductase-mediated lipid peroxidation, and Fenton chemistry. Cellular defence is organized around the system Xc-/GSH/GPX4 axis and GPX4-independent systems, including FSP1-CoQ10-NADPH, GCH1-BH4-DHFR, DHODH-CoQH2, and MBOAT1/2-mediated phospholipid remodelling. Ferroptosis is regulated by p53, NRF2, MAPK-AMPK signalling, hypoxia, mitochondrial metabolism, and immune cells such as macrophages. It contributes to cancer biology, cardiovascular and metabolic diseases, liver injury, neurological disorders, and inflammatory conditions. Therapeutic strategies include ferroptosis inducers, iron chelators, radical-trapping antioxidants, natural products, and nanomedicine, but biomarker validation and clinical translation remain unresolved.