ACSL4 dictates ferroptosis sensitivity by shaping cellular lipid composition

  • Nat Chem Biol. 2017 Jan;13(1):91-98. doi: 10.1038/nchembio.2239.
Sebastian Doll  1 ,  Bettina Proneth  1 ,  Yulia Y Tyurina  2 ,  Elena Panzilius  3 ,  Sho Kobayashi  1 ,  Irina Ingold  1 ,  Martin Irmler  4 ,  Johannes Beckers  4 ,  Michaela Aichler  5 ,  Axel Walch  5 ,  Holger Prokisch  6  7 ,  Dietrich Trümbach  1 ,  Gaowei Mao  2 ,  Feng Qu  2 ,  Hulya Bayir  2 ,  Joachim Füllekrug  8 ,  Christina H Scheel  3 ,  Wolfgang Wurst  1 ,  Joel A Schick  1 ,  Valerian E Kagan  2 ,  José Pedro Friedmann Angeli  1 ,  Marcus Conrad  1
Affiliations
  • 1. Institute of Developmental Genetics, Helmholtz Zentrum München, Neuherberg, Germany.
  • 2. Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
  • 3. Institute of Stem Cell Biology, Helmholtz Zentrum München, Neuherberg, Germany.
  • 4. Institute of Experimental Genetics, Helmholtz Zentrum München, Neuherberg, Germany.
  • 5. Institute of Pathology, Helmholtz Zentrum München, Neuherberg, Germany.
  • 6. Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany.
  • 7. Technische Universität München, Institute of Human Genetics, München, Germany.
  • 8. Department of Gastroenterology, University of Heidelberg, Heidelberg, Germany.
PMID: 27842070 DOI: 10.1038/nchembio.2239
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.