title: ACSL4 dictates ferroptosis sensitivity by shaping cellular lipid composition.
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.
authors.affiliation: Institute of Developmental Genetics, Helmholtz Zentrum München, Neuherberg, Germany.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Doll
authors.affiliation: Institute of Developmental Genetics, Helmholtz Zentrum München, Neuherberg, Germany.
authors.forename: Bettina
authors.initials: B
authors.lastname: Proneth
authors.affiliation: Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
authors.forename: Yulia Y
authors.initials: YY
authors.lastname: Tyurina
authors.affiliation: Institute of Stem Cell Biology, Helmholtz Zentrum München, Neuherberg, Germany.
authors.forename: Elena
authors.initials: E
authors.lastname: Panzilius
authors.affiliation: Institute of Developmental Genetics, Helmholtz Zentrum München, Neuherberg, Germany.
authors.forename: Sho
authors.initials: S
authors.lastname: Kobayashi
authors.affiliation: Institute of Developmental Genetics, Helmholtz Zentrum München, Neuherberg, Germany.
authors.forename: Irina
authors.initials: I
authors.lastname: Ingold
authors.affiliation: Institute of Experimental Genetics, Helmholtz Zentrum München, Neuherberg, Germany.
authors.forename: Martin
authors.identifier: http://orcid.org/0000-0003-3169-479X
authors.initials: M
authors.lastname: Irmler
authors.affiliation: Institute of Experimental Genetics, Helmholtz Zentrum München, Neuherberg, Germany.
authors.forename: Johannes
authors.initials: J
authors.lastname: Beckers
authors.affiliation: Institute of Pathology, Helmholtz Zentrum München, Neuherberg, Germany.
authors.forename: Michaela
authors.initials: M
authors.lastname: Aichler
authors.affiliation: Institute of Pathology, Helmholtz Zentrum München, Neuherberg, Germany.
authors.forename: Axel
authors.initials: A
authors.lastname: Walch
authors.affiliation: Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany.|Technische Universität München, Institute of Human Genetics, München, Germany.
authors.forename: Holger
authors.initials: H
authors.lastname: Prokisch
authors.affiliation: Institute of Developmental Genetics, Helmholtz Zentrum München, Neuherberg, Germany.
authors.forename: Dietrich
authors.initials: D
authors.lastname: Trümbach
authors.affiliation: Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
authors.forename: Gaowei
authors.initials: G
authors.lastname: Mao
authors.affiliation: Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
authors.forename: Feng
authors.initials: F
authors.lastname: Qu
authors.affiliation: Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
authors.forename: Hulya
authors.initials: H
authors.lastname: Bayir
authors.affiliation: Department of Gastroenterology, University of Heidelberg, Heidelberg, Germany.
authors.forename: Joachim
authors.initials: J
authors.lastname: Füllekrug
authors.affiliation: Institute of Stem Cell Biology, Helmholtz Zentrum München, Neuherberg, Germany.
authors.forename: Christina H
authors.initials: CH
authors.lastname: Scheel
authors.affiliation: Institute of Developmental Genetics, Helmholtz Zentrum München, Neuherberg, Germany.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Wurst
authors.affiliation: Institute of Developmental Genetics, Helmholtz Zentrum München, Neuherberg, Germany.
authors.forename: Joel A
authors.initials: JA
authors.lastname: Schick
authors.affiliation: Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
authors.forename: Valerian E
authors.initials: VE
authors.lastname: Kagan
authors.affiliation: Institute of Developmental Genetics, Helmholtz Zentrum München, Neuherberg, Germany.
authors.forename: José Pedro Friedmann
authors.initials: JP
authors.lastname: Angeli
authors.affiliation: Institute of Developmental Genetics, Helmholtz Zentrum München, Neuherberg, Germany.
authors.forename: Marcus
authors.initials: M
authors.lastname: Conrad
mesh_terms: D000818:Animals; D017209:Apoptosis; D016923:Cell Death / Q000187:drug effects; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D003066:Coenzyme A Ligases / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000378:metabolism*; D005260:Female; D005979:Glutathione Peroxidase / Q000172:deficiency / Q000378:metabolism*; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D009336:Necrosis; D000080662:Phospholipid Hydroperoxide Glutathione Peroxidase; D045162:Thiazolidinediones / Q000494:pharmacology
chemical_list: D007004:Hypoglycemic Agents; D045162:Thiazolidinediones; D000080662:Phospholipid Hydroperoxide Glutathione Peroxidase; D005979:Glutathione Peroxidase; C000611332:glutathione peroxidase 4, mouse; C581020:Acsl4 protein, mouse; D003066:Coenzyme A Ligases