Glutathione peroxidase 4 (GPX4), Acyl-CoA synthetase long-chain family member 4 (ACSL4), and Arachidonate 15-lipoxygenase (ALOX15) (GPX4/ACSL4/ALOX15)

The GPX4/ACSL4/ALOX15 axis represents the core regulatory machinery of ferroptosis, an iron-dependent form of regulated cell death characterized by the accumulation of lipid peroxides [2, 15]. Glutathione peroxidase 4 (GPX4) is the primary enzymatic defense against ferroptosis, utilizing glutathione to reduce toxic lipid hydroperoxides into non-toxic lipid alcohols [3, 11]. Conversely, Acyl-CoA synthetase long-chain family member 4 (ACSL4) and Arachidonate 15-lipoxygenase (ALOX15) are key pro-ferroptotic drivers. ACSL4 facilitates the incorporation of polyunsaturated fatty acids (PUFAs) into membrane phospholipids, providing the necessary substrates for peroxidation [15, 16]. ALOX15 then directly catalyzes the oxygenation of these PUFA-phospholipids to generate the lipid hydroperoxides that execute cell death [1, 17]. This regulatory triad is a major focus in oncology, where inducing ferroptosis via GPX4 inhibition (e.g., by RSL3 or Altretamine) can eradicate therapy-resistant cancer cells [13, 14]. In contrast, inhibiting the pro-ferroptotic enzymes ACSL4 or ALOX15 is being explored as a strategy to prevent pathological cell loss in neurodegenerative diseases and ischemia-reperfusion injury [18, 19]. The balance between these three enzymes determines a cell's sensitivity to ferroptotic stimuli, making them critical biomarkers for patient stratification in ferroptosis-targeted therapies [12, 16].

Other names

PHGPXPhospholipid hydroperoxide glutathione peroxidaseFACL4LACS415-LOX-112/15-LOXArachidonate 15-lipoxygenaseFerroptosis regulatory axis

Induction of ferroptosis via direct inhibition of GPX4 antioxidant activity, or prevention of ferroptosis via inhibition of ACSL4-mediated phospholipid synthesis and ALOX15-mediated lipid peroxidation.