Ferroptotic lipid peroxidation pathway

The ferroptotic lipid peroxidation pathway is a regulated cell death process characterized by the iron-dependent accumulation of lipid peroxides, particularly within polyunsaturated fatty acid-containing phospholipids (PUFA-PLs) [1, 4]. This pathway is distinct from apoptosis and necrosis, relying on the failure of antioxidant defense systems, most notably the glutathione peroxidase 4 (GPX4) enzyme, to neutralize lipid reactive oxygen species [1, 3]. Key regulatory components include the system Xc- cystine/glutamate antiporter, which provides the precursor for glutathione synthesis, and enzymes like ACSL4 and LPCAT3 that incorporate oxidizable fatty acids into membranes [3, 4]. In oncology, the pathway is targeted for induction to eliminate drug-resistant or mesenchymal-state cancer cells [5, 8]. Conversely, in conditions such as neurodegeneration, ischemia-reperfusion injury, and organ failure, the pathway is targeted for inhibition to prevent pathological cell loss [1, 2, 4]. Therapeutic strategies involve small-molecule inducers (e.g., erastin, RSL3) or inhibitors (e.g., ferrostatin-1, liproxstatin-1) that modulate iron levels, glutathione availability, or radical-trapping capacity [1, 5, 6].

Other names

Ferroptosis pathwayIron-dependent lipid peroxidation pathwayGPX4-regulated cell death pathway

Induction of iron-dependent lipid peroxidation through GPX4 inhibition or glutathione depletion; or inhibition of lipid peroxidation using radical-trapping antioxidants or iron chelators.