ACSL4 dictates ferroptosis sensitivity by shaping cellular lipid composition
- PMID: 27842070
- PMCID: PMC5610546
- DOI: 10.1038/nchembio.2239
ACSL4 dictates ferroptosis sensitivity by shaping cellular lipid composition
Abstract
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.
Conflict of interest statement
Competing financial interests
The authors declare no competing financial interests.
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Comment in
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Ferroptosis: Oxidized PEs trigger death.Nat Chem Biol. 2017 Jan;13(1):4-5. doi: 10.1038/nchembio.2261. Epub 2016 Nov 14. Nat Chem Biol. 2017. PMID: 27842067 No abstract available.
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