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).
Organ Systems
immune-hematologic
nervous
cardiovascular
renal
digestive
Pathway Steps
labile-iron pool (Fe²⁺) + H₂O₂ → Fenton •OH radical — via iron-dependent radical initiation; opposed by iron chelators + ferritin sequestration. Ferroptosis is iron-dependent: the labile Fe²⁺ pool reacts with peroxide via Fenton chemistry to generate the hydroxyl radical (•OH), which initiates lipid radical chains. This iron requirement is why iron chelators block ferroptosis and why iron-loaded or rapidly proliferating cells are especially vulnerable.
PUFA-CoA → PE-PUFA (membrane phospholipid) — via ACSL4 + LPCAT3 incorporate AA / AdA into PE; ACSL4-low cells are ferroptosis-resistant. Ferroptosis needs a specific lipid substrate: ACSL4 and LPCAT3 esterify polyunsaturated fatty acids (arachidonic/adrenic acid) into membrane phosphatidylethanolamine. Those PUFA double bonds are the oxidizable fuel — so ACSL4-low cells are ferroptosis-resistant, and membrane PUFA content tunes sensitivity.
PE-PUFA + •OH → PE-PUFA-OOH (lipid hydroperoxide) — via autoxidation OR enzymatic via 15-LOX / ALOX15. The membrane PUFA-PE is oxidized to lipid hydroperoxides (PE-PUFA-OOH) — both by radical autoxidation and enzymatically by 15-lipoxygenase (ALOX15). Once started the chain self-propagates: each peroxyl radical abstracts another bis-allylic hydrogen, spreading damage across the bilayer.
PE-PUFA-OOH + 2 GSH → PE-PUFA-OH + GSSG — via GPX4 (selenoprotein) — the master lipid peroxide reductase; loss = ferroptosis. The master defense is GPX4, a selenocysteine glutathione peroxidase that reduces lethal lipid hydroperoxides to harmless alcohols using two GSH. Direct GPX4 inhibition (RSL3) forces ferroptosis, and GPX4’s selenium requirement ties the pathway to selenium status and the wider antioxidant network.
extracellular cystine → intracellular cysteine → GSH — via SLC7A11 (xCT, system xc⁻); erastin / sulfasalazine block this. GPX4 needs glutathione, whose synthesis is cysteine-limited. The cystine/glutamate antiporter system xc⁻ (SLC7A11/xCT) imports cystine for conversion to cysteine; blocking it (erastin, sulfasalazine, or glutamate excess) starves GSH synthesis and triggers ferroptosis — the classic indirect route to GPX4 failure.
CoQ10 + FSP1 (AIFM2) → CoQ10H₂ (reduced) at plasma membrane — via GPX4-independent radical-trapping; parallel defense. A parallel, GPX4-independent guard works at the plasma membrane: FSP1 (AIFM2) regenerates reduced CoQ10 (ubiquinol), a lipophilic radical-trapping antioxidant. This axis explains why some cells resist GPX4 inhibition — so the GPX4/GSH and FSP1/CoQ10 systems jointly set the ferroptotic threshold.
PE-PUFA-OOH (unreduced) → membrane disruption → ferroptotic cell death — via amplification cascade; characteristic mitochondrial shrinkage on EM. If hydroperoxides outpace these defenses, accumulating oxidized lipids and their reactive breakdown products (e.g. 4-HNE) rupture membrane integrity, producing the characteristic ferroptotic morphology (shrunken mitochondria with dense cristae). Lipid peroxidation is thus both trigger and executioner.