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ACSL4 dictates ferroptosis sensitivity by shaping cellular lipid composition.

Nat. Chem. Biol. 13, 91-98 (2017)
Postprint Research data DOI PMC
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© 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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Publication type Article: Journal article
Document type Scientific Article
Keywords Placebo-controlled Trial; Glutathione-peroxidase 4; Focal Cerebral-ischemia; Coa Synthetase 4; Nonalcoholic Steatohepatitis; Therapeutic Target; Death; Pioglitazone; Cancer; Cells
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