Figure 1.

The essence of ferroptosis is iron-dependent lipid peroxidation. Fe³⁺ circulating in the bloodstream is endocytosed as the Fe³⁺-TF-TFR1 complex. In the cell, Fe³⁺ is dissociated from TF and is reduced to Fe²⁺ by STEAP3, and Fe²⁺ is stored in ferritin. NCOA4 promotes Fe²⁺ to be released from ferritin and enters the labile iron pool, which participates in multiple cellular processes and the Fenton reaction. The phospholipids containing PUFA chain are generated from PUFAs by ACSL4 and LPCAT3, which are peroxidized through the Fenton reaction to form toxic lipid hydroperoxides. The process of lipid peroxidation is antagonized by the GSH-GPX4 pathway. System x_c⁻ transports cystine into the cell, which is reduced to cysteine, the rate-limiting precursor of GSH. GPX4 uses GSH as a cofactor to convert lipid hydroperoxides to nontoxic lipid alcohols, thereby inhibiting ferroptosis. ACSL4, acyl-CoA synthetase long-chain family member 4; Fe³⁺, ferric iron; Fe²⁺, ferrous iron; GPX4, glutathione peroxidase 4; GSH, glutathione; LPCAT3, lysophosphatidylcholine acyltransferase 3; NCOA4, nuclear receptor coactivator 4; PLOOH, phospholipid hydroperoxides; PL-PUFA, phospholipid containing polyunsaturated fatty acid chain; PUFA, polyunsaturated fatty acid; SLC40A1, solute carrier family 40 member 1 (also known as ferroportin); STEAP3, six-transmembrane epithelial antigen of prostate 3; TF, transferrin; TFR1, TF receptor 1.