Mechanism of ferroptosis. (a) Tf binds ferric ions and forms a Tf-TFR1 complex with TFR1. The following endocytosis into acidic endosomes, ferric ions are reduced into ferrous ions and transported by DMT1 to labile iron pools in the cytoplasm. The accumulation of intracellular ferrous ions promotes lipid peroxidation, leading to the production of ROS and ultimately to ferroptosis. (b) System xc-exchanges intracellular glutamate for extracellular cystine in a 1:1 ratio, which is then synthesized into GSH by GCL and GSS. GSH is a reducing cofactor for glutathione peroxidase (GPX4), a membrane lipid repair enzyme that eliminates lipid hydroperoxides to protect against ferroptosis. (c) Dihydroorotate Dehydrogenase (DHODH) in the mitochondrial membrane resists ferroptosis by oxidizing dihydroorotate (DHO) to orotic acid (OA) and reducing ubiquinone (CoQ10) to Dihydroubiquinone (CoQH2). (d) Ferroptosis suppressor protein 1 (FSP1) converts ubiquinone into ubiquinol and generates a lipophilic, radical-trapping antioxidant (RTA) that prevents lipid peroxide formation and inhibits ferroptosis. (e) Polyunsaturated fatty acids (PUFA) are substrates for lipid peroxidation and react with acyl-CoA synthetase long-chain family member-4 (ACSL4) to generate Malondialdehyde (MDA) and 4-hydroxynonenal (4-HNE), eventually leading to ferroptosis.