Fig. 1

Timeline of the identification and characterization of ferroptosis, and the underlying mechanisms. a, Timeline depicting the past, present, and future of ferroptosis. The first time period (1980–2012) ended with the term “ferroptosis” being coined by Dixon et al. in 2012. The present period (2012–2023) developed rapidly, with important details emerging such as the GCH1-BH₄ and DHODH-CoQ₁₀ pathways. The future (2023-?) is expected to bring numerous new applications for targeting ferroptosis. b, Three pathways mediate ferroptosis, including iron metabolism, redox, and lipid metabolism. Dysregulation of oxidative-reductive systems, iron metabolism, and/or peroxidation of PUFAs can induce ferroptosis. ACSL4, acyl-CoA synthetase long-chain family member 4; BH₄, tetrahydrobiopterin; CBS, cystathionine beta-synthase; CD36, cluster differentiation 36; CoQ₁₀, coenzyme Q₁₀; CTH, cystathionine gamma-lyase; DHODH, dihydroorotate dehydrogenase; DMT1, proton-coupled divalent metal ion transporter 1; FPN, ferroportin; FSP1, ferroptosis suppressor protein 1; GCH1, GTP cyclohydrolase 1; GPX4, glutathione peroxidase 4; GSH, glutathione; GSSG, glutathione disulfide; HO-1, heme oxygenase 1; Keap1, Kelch-like ECH-associated protein 1; LOX, lipoxygenase; LPCAT, lysophosphatidylcholine acyltransferase; MUFA, monounsaturated fatty acid; NCOA4, nuclear receptor coactivator 4; Nrf2, nuclear factor erythroid 2-related factor 2; PL-PUFA, phospholipid-containing polyunsaturated fatty acid; PUFA, polyunsaturated fatty acid; RNF217, E3 ubiquitin protein ligase RNF217; SCD1, stearoyl-coenzyme A desaturase 1; SLC, solute carrier family; SQS, squalene synthase; STEAP, 6-transmembrane epithelial antigen of the prostate metalloreductase family; TF, transferrin; TFR1, transferrin receptor protein 1; TRPML, lysosomal cation channel mucolipin. Created with BioRender.com