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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)
Verlagsversion Postprint Forschungsdaten DOI
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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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter Placebo-controlled Trial; Glutathione-peroxidase 4; Focal Cerebral-ischemia; Coa Synthetase 4; Nonalcoholic Steatohepatitis; Therapeutic Target; Death; Pioglitazone; Cancer; Cells
ISSN (print) / ISBN 1552-4450
e-ISSN 1552-4469
Quellenangaben Band: 13, Heft: 1, Seiten: 91-98 Artikelnummer: , Supplement: ,
Verlag Nature Publishing Group
Verlagsort Basingstoke
Begutachtungsstatus Peer reviewed