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Doll, S. ; Proneth, B. ; Tyurina, A.A.* ; Panzilius, E. ; Kobayashi, S. ; Ingold, I. ; Irmler, M. ; Beckers, J. ; Aichler, M. ; Walch, A.K. ; Prokisch, H. ; Trümbach, D. ; Mao, G.* ; Qu, F.* ; Bayir, H.* ; Füllekrug, J.* ; Scheel, C. ; Wurst, W. ; Schick, J. ; Kagan, V.E.* ; Friedmann Angeli, J.P.F. ; Conrad, M.

ACSL4 dictates ferroptosis sensitivity by shaping cellular lipid composition.

Nat. Chem. Biol. 13, 91-98 (2017)
Postprint Research data DOI PMC
Open Access Green
© 2016 Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved.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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Publication type Article: Journal article
Document type Scientific Article
Keywords Placebo-controlled Trial; Glutathione-peroxidase 4; Focal Cerebral-ischemia; Coa Synthetase 4; Nonalcoholic Steatohepatitis; Therapeutic Target; Death; Pioglitazone; Cancer; Cells
Language
Publication Year 2017
Prepublished in Year 2016
HGF-reported in Year 2016
ISSN (print) / ISBN 1552-4450
e-ISSN 1552-4469
Journal Nature Chemical Biology
Quellenangaben Volume: 13, Issue: 1, Pages: 91-98 Article Number: , Supplement: ,
Publisher Nature Publishing Group
Publishing Place Basingstoke
Reviewing status Peer reviewed
Institute(s) Institute of Developmental Genetics (IDG)
Institute of Experimental Genetics (IEG)
Institute of Stem Cell Research (ISF)
Research Unit Analytical Pathology (AAP)
Institute of Human Genetics (IHG)
Institute of Molecular Toxicology and Pharmacology (TOX)
POF-Topic(s) 30204 - Cell Programming and Repair
30201 - Metabolic Health
30205 - Bioengineering and Digital Health
30501 - Systemic Analysis of Genetic and Environmental Factors that Impact Health
30203 - Molecular Targets and Therapies
Research field(s) Genetics and Epidemiology
Stem Cell and Neuroscience
Enabling and Novel Technologies
PSP Element(s) G-500500-001
G-500600-004
G-500890-001
G-500390-001
G-500700-001
G-505200-001
DOI 10.1038/nchembio.2239
WOS ID WOS:000393267200018
Scopus ID 84995468814
PubMed ID 27842070
Erfassungsdatum 2016-11-17
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