Figure 1.

Major sources of intracellular reactive oxygen species (ROS) production and their convergence to ferroptosis through generation of H₂O₂. (a) In the mitochondria, ETC-produced superoxide is converted to hydrogen peroxide by SOD2 and SOD1. Cytochrome C, located in the mitochondrial IMS, may have a dual role by scavenging superoxide or interacting with peroxide and contributing to the cardiolipin peroxidation. Mitochondrial activity by supporting lipid biosynthesis may enhance ferroptosis. (b) Excessive protein refolding in ER increases PDI/Ero1a activities resulting in a rise of H₂O₂ production, calcium efflux, NADPH oxidase activation, and general ER stress linked to inflammation. (c) Ferrous iron overload, elevated levels of H₂O₂, and GPX4 deficiency cause accumulation of lipid peroxides and initiation of ferroptotic cell death. ACSL4 and LPCAT3 catalyze incorporation of PUFA into membranes, thereby sensitizing them to ferroptosis. (d) In peroxisomes, ROS are primarily produced by fatty acid beta-oxidation catalyzed by ACOX. Abbreviations: IMS—intermembrane space; ETC—electron transport chain; SOD1—Cu,Zn superoxide dismutase; SOD2—Mn superoxide dismutase; PDI—protein disulfide isomerase; ERO1a—Endoplasmic reticulum oxidoreductase 1 alpha; NOX—NADPH oxidase; GPX4—Glutathione peroxidase 4; PERK—protein kinase RNA-like endoplasmic reticulum kinase; ATF6—activating transcription factor 6; IRE1—inositol-requiring enzyme 1; NFkB—nuclear factor kappa-light-chain-enhancer of activated B cells; TRAF2—TNF receptor associated factor 2; JNK—c-Jun N-terminal kinase. ACSL4—Acyl-CoA synthetase long chain family member 4; LPCAT3—Lysophosphatidylcholine acyltransferase 3; PUFA—polyunsaturated fatty acids; ACOX—Acyl-CoA oxidase.