Fig. 1

Mechanisms of ferroptosis. Ferroptosis is caused by iron-dependent lipid peroxidation. The extracellular circulating iron ions (Fe³⁺) are transferred into cells via TFRC, catalyzed to Fe²⁺ by the reductase STEAP3 in endosomes, and released into the cytoplasm by DMT1 for cellular processes. The usable iron ions form a labile iron pool or are stored in ferritin. Excess iron ions are translocated into the extracellular circulation by FPN or prominin-2-mediated ferritin-containing MVBs. The Fenton reaction induced by labile iron generates ROS and activates iron-containing enzymes such as ALOXs and POR, resulting in lipid peroxidation and membrane damage. NCOA4-mediated ferritinophagy releases iron from ferritin, leading to membrane oxidative damage and ferroptosis. Cystine is imported into cells by the transmembrane glutamate/cystine antiporter system Xc⁻ and is subsequently oxidized to cysteine. Cells synthesize GSH using cysteine, glutamate, and glycine as substrates under the catalysis of GCL and GSS. Using GSH as a cofactor, GPX4 reduces PUFA-PL-OOH to non-toxic PUFA-PL-OH and exerts antioxidant effects, which alleviates membrane damage caused by lipid peroxidation, thus inhibiting ferroptosis. FSP1-CoQH2, DHODH-CoQH2, FSP1-VKH2, and GCH1-BH4 signaling also inhibit lipid peroxidation-induced ferroptosis. ACSL4 acyl-CoA synthetase long-chain family member 4, ALOXs lipoxygenases, BH4 tetrahydrobiopterin, CoQ₁₀ coenzyme Q₁₀, DHODH dihydroorotate dehydrogenase, DMT1 ferrous ion membrane transport protein 1, FPN ferroportin, FSP1 ferroptosis suppressor protein 1/AIFM2, GCH1 GTP cyclohydrolase 1, GCL glutamate–cysteine ligase, GSS glutathione synthase, GPX4 glutathione peroxidase 4, GR glutathione reductase, GSH glutathione, GSSG oxidized glutathione disulfide, LPCAT3 lysophosphatidylcholine acyltransferase 3, MVBs multivesicular bodies, POR cytochrome P450 oxidoreductase, PROM2 prominin-2, PUFA polyunsaturated fatty acid, PUFA-PLs polyunsaturated fatty-acid-containing phospholipids, PUFA-PL-OH PUFA phospholipid alcohols, PUFA-PL-OOH phospholipid with peroxidized polyunsaturated fatty acyl tail, ROS reactive oxygen species, STEAP3 six-transmembrane epithelial antigen of the prostate 3, TFRC transferrin receptor, VK vitamin K, VKH2 reduced form of vitamin K