{"entity":{"id":"ferroptosis-cell-death","kind":"pathway","name":"Ferroptosis & regulated cell death","aka":[],"tldr":"Cells can die in several programmed ways. Beyond the classic apoptosis, ferroptosis kills through iron-driven fat oxidation, and drug-resistant, mesenchymal cancer cells turn out to be unusually prone to it.","summary":"Ferroptosis is iron-dependent lipid peroxidation restrained by GPX4 (using glutathione from the cystine transporter SLC7A11/xCT) and by FSP1. Therapy-persistent, mesenchymal, and dedifferentiated cancer cells depend on GPX4; radiation and some immunotherapies act partly via ferroptosis. Necroptosis (RIPK3/MLKL) and pyroptosis (gasdermins) are inflammatory death modes that can be immunogenic. No ferroptosis inducer is approved; GPX4 inhibitors lack drug-like properties, so xCT inhibition, cyst(e)inase, and sulfasalazine repurposing are the clinical routes.","asOf":"2026-09-08","wikipedia":"https://en.wikipedia.org/wiki/Ferroptosis","links":[{"label":"Stockwell, Ferroptosis turns 10 (Cell 2022)","url":"https://doi.org/10.1016/j.cell.2022.06.003"},{"label":"Viswanathan et al., Dependency of a therapy-resistant state on a lipid peroxidase pathway (Nature 2017)","url":"https://doi.org/10.1038/nature23007"}],"tags":["mechanism"],"related":[],"cancers":[],"sections":[],"technologies":[],"targets":["bcl2"],"drugs":["venetoclax"],"companies":[],"institutions":["mskcc","stanford","broad-institute"],"pathways":["apoptosis-bcl2","emt","cancer-metabolism"],"terms":["resisting-cell-death","resistance"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":["paper-stockwell-cell","paper-viswanathan-nature"],"journals":[],"dependsOn":[],"notes":["Leading programmes: Stockwell (Columbia, coined ferroptosis); Dixon (Stanford); Schreiber (Broad) on persister-cell GPX4 dependence; Jiang (MSK) on ferroptosis in immunotherapy."],"analogy":"Ferroptosis is rust. Iron plus oxygen eats through the cell's membranes unless an antioxidant crew (GPX4) keeps repainting them. Cells that changed shape to dodge chemotherapy have thinner paint.","nodes":[{"id":"cys","label":"Cystine import (SLC7A11)","x":15,"y":30},{"id":"gsh","label":"Glutathione","x":40,"y":30},{"id":"gpx4","label":"GPX4","x":65,"y":30},{"id":"lpo","label":"Lipid peroxidation","x":65,"y":70},{"id":"iron","label":"Labile iron (Fenton)","x":35,"y":70},{"id":"ferro","label":"Ferroptosis","x":90,"y":70},{"id":"mes","label":"Mesenchymal / persister state","x":90,"y":30},{"id":"apo","label":"Apoptosis (BCL-2 family)","x":15,"y":90,"targetId":"bcl2"}],"edges":[{"from":"cys","to":"gsh","type":"activates"},{"from":"gsh","to":"gpx4","type":"activates"},{"from":"gpx4","to":"lpo","type":"inhibits"},{"from":"iron","to":"lpo","type":"activates"},{"from":"lpo","to":"ferro","type":"activates"},{"from":"mes","to":"gpx4","type":"activates"}],"interventions":["xCT inhibitors, cyst(e)inase, sulfasalazine repurposing (early trials)","Radiotherapy and IFN-γ from T cells induce lipid peroxidation","BH3 mimetics (venetoclax) exploit apoptosis; MCL-1 inhibitors in development","Persister-cell targeting after EGFR/ALK inhibitors (preclinical)"]},"route":"/pathways/ferroptosis-cell-death/","neighbours":{"target":[{"id":"bcl2","kind":"target","name":"BCL-2","route":"/targets/bcl2/"}],"drug":[{"id":"venetoclax","kind":"drug","name":"Venetoclax","route":"/drugs/venetoclax/"}],"institution":[{"id":"broad-institute","kind":"institution","name":"Broad Institute of MIT and Harvard","route":"/institutions/broad-institute/"},{"id":"mskcc","kind":"institution","name":"Memorial Sloan Kettering Cancer Center","route":"/institutions/mskcc/"},{"id":"stanford","kind":"institution","name":"Stanford Health Care / Stanford Cancer Institute","route":"/institutions/stanford/"}],"pathway":[{"id":"cancer-metabolism","kind":"pathway","name":"Cancer metabolism","route":"/pathways/cancer-metabolism/"},{"id":"drug-tolerant-persisters","kind":"pathway","name":"Drug-tolerant persister cells","route":"/pathways/drug-tolerant-persisters/"},{"id":"emt","kind":"pathway","name":"Epithelial-mesenchymal transition & drug efflux","route":"/pathways/emt/"},{"id":"apoptosis-bcl2","kind":"pathway","name":"Intrinsic apoptosis (BCL-2 family)","route":"/pathways/apoptosis-bcl2/"},{"id":"keap1-nrf2","kind":"pathway","name":"KEAP1-NRF2 antioxidant pathway","route":"/pathways/keap1-nrf2/"},{"id":"lipid-metabolism-cancer","kind":"pathway","name":"Lipid synthesis, uptake & cholesterol","route":"/pathways/lipid-metabolism-cancer/"}],"term":[{"id":"apoptosis","kind":"term","name":"Apoptosis","route":"/terms/apoptosis/"},{"id":"resistance","kind":"term","name":"Drug resistance (primary and acquired)","route":"/terms/resistance/"},{"id":"resisting-cell-death","kind":"term","name":"Hallmark: resisting cell death","route":"/terms/resisting-cell-death/"}],"paper":[{"id":"paper-viswanathan-nature","kind":"paper","name":"Dependency of a therapy-resistant state of cancer cells on a lipid peroxidase pathway","route":"/key-papers/paper-viswanathan-nature/"},{"id":"paper-stockwell-cell","kind":"paper","name":"Ferroptosis turns 10: Emerging mechanisms, physiological functions, and therapeutic applications","route":"/key-papers/paper-stockwell-cell/"}],"idea":[{"id":"idea-ferroptosis-persisters","kind":"idea","name":"Kill drug-tolerant persisters through ferroptosis","route":"/ideas/idea-ferroptosis-persisters/"}]}}