Fig. 1.

Core mechanism of ferroptosis. Ferroptosis is an iron-dependent form of regulated cell death. Fe²⁺ can participate in the Fenton reaction and induce lipid peroxidation. LTF and TF-mediated iron uptake and NCOA4-mediated ferritin degradation can promote ferroptosis, while the iron exporter SLC40A1 is a repressor of ferroptosis. GSH-dependent system (SLC7A11-GSH-GPX4 pathway) and GSH-independent system (CoQ, BH4, and ESCT-III pathway) inhibit ferroptotic cell death through suppressing lipid peroxidation or membrane damage. ACSL4, LPCAT3, and ALOX promote lipid peroxidation on the membrane. In addition, POR and NOXs also contribute to lipid peroxidation in a context-dependent manner. The complex regulation of SLC7A11 or GPX4 by multiple mechanism affects ferroptosis sensitivity (see text). Abbreviations: ACO1, aconitase 1; ACSL4, acyl-CoA synthetase long-chain family member 4; ALOXs, lipoxygenases; AIFM2, apoptosis-inducing factor mitochondria-associated 2; ATF3, activating transcription factor 3; ATF4, activating transcription factor 4; BECN1, beclin 1; CBS, cystathionine beta-synthase; CoQ10, coenzyme Q10; CoQ10H2, reduced coenzyme Q10; CREB, CAMP responsive element binding protein; Cys, cysteine; Cys2, cystine; DHODH, dihydroorotate dehydrogenase; ESCRT-III, endosomal sorting complexes required for transport-III; GCLC, glutamate-cysteine ligase catalytic subunit; Glu, glutamate; Gly, glycine; GPX4, glutathione peroxidase 4; GSH, glutathione; GSS, glutathione synthetase; GSR, glutathione reductase; GSSG, oxidized glutathione; HSPA5, heat shock protein family A member 5; HSP90, heat shock protein 90; IREB2, iron-responsive element binding protein 2; LCN2, lipocalin 2; LIP, labile iron pool; LPCAT3, lysophosphatidic transferase 3; LTF, lactotransferrin; LSH, lymphoid-specific helicase; Met, methionine; NFE2L2, nuclear factor erythroid 2-like 2; NCOA4, nuclear receptor coactivator 4; NOXs, NADPH oxidases; OTUB1, OTU deubiquitinase, ubiquitin aldehyde binding 1; POR, cytochrome P450 oxidoreductase; PUFAs, polyunsaturated fatty acid; PUFAs-CoA, polyunsaturated fatty acids-CoA; PUFA-PLs, phospholipids containing polyunsaturated fatty acids; ROS, reactive oxygen species; SLC3A2, solute carrier family 3 member 2; SLC40A1, solute carrier family 40 member 1; SLC7A11, solute carrier family 7 member 11; TF, transferrin; TFRC, transferrin receptor; TP53, tumor protein p53; USP35, ubiquitin specific peptidase 35