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Friedmann Angeli, J.P.F.
ACSL4 dictates ferroptosis sensitivity by shaping cellular lipid composition.
Nat. Chem. Biol.
, 91-98 (2017)
Open Access Green
as soon as is submitted to ZB.
© 2016 Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved.Ferroptosis is a form of regulated necrotic cell death controlled by glutathione peroxidase 4 (GPX4). At present, mechanisms that could predict sensitivity and/or resistance and that may be exploited to modulate ferroptosis are needed. We applied two independent approaches—a genome-wide CRISPR-based genetic screen and microarray analysis of ferroptosis-resistant cell lines—to uncover acyl-CoA synthetase long-chain family member 4 (ACSL4) as an essential component for ferroptosis execution. Specifically, Gpx4–Acsl4 double-knockout cells showed marked resistance to ferroptosis. Mechanistically, ACSL4 enriched cellular membranes with long polyunsaturated ω6 fatty acids. Moreover, ACSL4 was preferentially expressed in a panel of basal-like breast cancer cell lines and predicted their sensitivity to ferroptosis. Pharmacological targeting of ACSL4 with thiazolidinediones, a class of antidiabetic compound, ameliorated tissue demise in a mouse model of ferroptosis, suggesting that ACSL4 inhibition is a viable therapeutic approach to preventing ferroptosis-related diseases.
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Article: Journal article
Placebo-controlled Trial; Glutathione-peroxidase 4; Focal Cerebral-ischemia; Coa Synthetase 4; Nonalcoholic Steatohepatitis; Therapeutic Target; Death; Pioglitazone; Cancer; Cells
Institute of Developmental Genetics (IDG)
Institute of Experimental Genetics (IEG)
Institute of Stem Cell Research (ISF)
Research Unit Analytical Pathology (AAP)
Institute of Human Genetics (IHG)
Institute of Molecular Toxicology and Pharmacology (TOXI)