Authors: Sebastian Doll, Bettina Proneth, Yulia Y Tyurina, Elena Panzilius, Sho Kobayashi, Irina Ingold, Martin Irmler, Johannes Beckers, Michaela Aichler, Axel Walch, Holger Prokisch, Dietrich Trümbach, Gaowei Mao, Feng Qu, Hulya Bayir, Joachim Füllekrug, Christina H Scheel, Wolfgang Wurst, Joel A Schick, Valerian E Kagan, José Pedro Friedmann Angeli & Marcus Conrad
Summary:
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.
Source:
Nature Chemical Biology; November 14, 2016