Journal
NATURE CHEMICAL BIOLOGY
Volume 13, Issue 1, Pages 91-98Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/NCHEMBIO.2239
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Funding
- Deutsche Forschungsgemeinschaft (DFG) [CO 291/2-3, CO 291/5-1]
- Japan Society for the Promotion of Science (JSPS)
- Human Frontier Science Program (HFSP) [RGP0013]
- German Bundesministerium fur Bildung und Forschung (BMBF) through the European E-Rare Network for mitochondrial disorders GENOMIT [01GM1603]
- National Institute of Health (NIH) [P01HL114453, U19AI068021, NS076511, NS061817, ES020693]
- Bavarian Ministry of Economic Affairs (m4 Award)
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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 co6 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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