Category: cell_death
Ferroptosis is an iron-dependent regulated cell death driven by lethal lipid peroxidation — distinct from apoptosis (no caspases / no MOMP), necroptosis (RIPK3/MLKL-independent), and pyroptosis (no gasdermin). Mechanism: (1) iron supply — labile-iron pool drives Fenton chemistry (Fe²⁺ + H₂O₂ → Fe³⁺ + •OH + OH⁻) → lipid radical initiation. (2) Substrate — polyunsaturated fatty acid (PUFA) phospholipids (especially PE-AA, PE-AdA) incorporated by ACSL4/LPCAT3 → peroxidation by LOX or autoxidation → PE-AA-OOH. (3) Defense system 1 — GPX4 (selenoprotein) uses GSH to reduce PE-AA-OOH → PE-AA-OH (non-lethal); loss of GPX4 is sufficient to trigger ferroptosis. GSH supply depends on SLC7A11 (xCT, system xc⁻) cystine import — erastin blocks SLC7A11, RSL3 blocks GPX4 directly. (4) Defense system 2 — FSP1 (AIFM2) → CoQ10 + vitamin E reduction → independent of GSH. (5) Defense system 3 — DHODH-CoQ10 in mitochondria. p53-SLC7A11 axis is a major regulator. Clinical relevance: cancer (Ras-mutant cells are sensitive — therapeutic opportunity), neurodegeneration (Parkinson nigral dopamine neurons accumulate iron + lipid peroxides), I/R injury (cardiac, renal, brain), iron-overload hepatopathy, hemoglobinopathies. Therapeutic landscape: ferrostatin-1 + liproxstatin-1 (radical-trapping antioxidants — preclinical); CoQ10, vitamin E, selenium support endogenous defenses; sorafenib + sulfasalazine + artemisinin trigger ferroptosis (cancer angle); deferiprone iron chelation in some contexts. Cross-links: [[ros_oxidative_stress]] (lipid radicals), [[iron_metabolism]] (Fe²⁺ supply), [[glutathione_metabolism]] (GSH → GPX4), [[nrf2_keap1_antioxidant_response]] (counter-regulatory).