2. Academic Validation
  3. ACSL4 dictates ferroptosis sensitivity by shaping cellular lipid composition

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

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.

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