Fig. 1. Mechanisms of ferroptosis.

The conversion of PUFAs to PL-PUFAs can be mediated by ACSL4 and LPCAT3. PL-PUFAs can be easily converted to PL-PUFA-OOH through various pathways, which can cause lipid peroxidation and ferroptosis. Extracellular Fe³⁺ enters the cell by binding to TF and undergoes reduction or ferritinophagy, ultimately converting into Fe²⁺ and forming the LIP. When LIP becomes overloaded with iron, it becomes prone to a Fenton reaction, facilitating lipid peroxidation and thereby triggering ferroptosis. The cysteine transported into cells by SLC7A11 can be converted into cystine, which is an essential component of GSH. GSH, mediated by GPX4, can be transformed into GSSG while reducing PL-PUFA-OOH to PL-PUFA-OH, thereby inhibiting ferroptosis. Abbreviations: PUFAs, polyunsaturated fatty acids; CoA, coenzyme A; PL-PUFAs, phospholipid-containing PUFAs; ACSL4, acyl-CoA synthetase long-chain family member 4; LPCAT3, lysophosphatidylcholine acyltransferase 3; TF, transferrin; TFR1, transferrin receptor 1; STEAP3, iron oxide reductase steam 3; DMT1, divalent metal transporter 1; NCOA4, nuclear receptor coactivator 4; LIP, labile iron pool; SLC7A11, solute carrier family 7 member 11; SLC3A2, solute carrier family 3 member 2; GSH, glutathione; GSSG, Oxidized glutathione; GPX4, glutathione peroxidase 4.