title: Oxidized arachidonic and adrenic PEs navigate cells to ferroptosis.
abstract: Enigmatic lipid peroxidation products have been claimed as the proximate executioners of ferroptosis-a specialized death program triggered by insufficiency of glutathione peroxidase 4 (GPX4). Using quantitative redox lipidomics, reverse genetics, bioinformatics and systems biology, we discovered that ferroptosis involves a highly organized oxygenation center, wherein oxidation in endoplasmic-reticulum-associated compartments occurs on only one class of phospholipids (phosphatidylethanolamines (PEs)) and is specific toward two fatty acyls-arachidonoyl (AA) and adrenoyl (AdA). Suppression of AA or AdA esterification into PE by genetic or pharmacological inhibition of acyl-CoA synthase 4 (ACSL4) acts as a specific antiferroptotic rescue pathway. Lipoxygenase (LOX) generates doubly and triply-oxygenated (15-hydroperoxy)-diacylated PE species, which act as death signals, and tocopherols and tocotrienols (vitamin E) suppress LOX and protect against ferroptosis, suggesting a homeostatic physiological role for vitamin E. This oxidative PE death pathway may also represent a target for drug discovery.
authors.affiliation: Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.|Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.|Department of Chemistry, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.|Department of Radiation Oncology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
authors.forename: Valerian E
authors.initials: VE
authors.lastname: Kagan
authors.affiliation: Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.|Department of Critical Care Medicine, 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: Institute of Developmental Genetics, Helmholtz Zentrum München, Neuherberg, Germany.
authors.forename: Jose Pedro Friedmann
authors.initials: JP
authors.lastname: Angeli
authors.affiliation: Institute of Developmental Genetics, Helmholtz Zentrum München, Neuherberg, Germany.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Doll
authors.affiliation: Department of Cell Biology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
authors.forename: Claudette St
authors.initials: CS
authors.lastname: Croix
authors.affiliation: Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
authors.forename: Haider Hussain
authors.initials: HH
authors.lastname: Dar
authors.affiliation: Department of Computational and Systems Biology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
authors.forename: Bing
authors.initials: B
authors.lastname: Liu
authors.affiliation: Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
authors.forename: Vladimir A
authors.initials: VA
authors.lastname: Tyurin
authors.affiliation: Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
authors.forename: Vladimir B
authors.initials: VB
authors.lastname: Ritov
authors.affiliation: Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
authors.forename: Alexandr A
authors.initials: AA
authors.lastname: Kapralov
authors.affiliation: Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
authors.forename: Andrew A
authors.initials: AA
authors.lastname: Amoscato
authors.affiliation: Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
authors.forename: Jianfei
authors.initials: J
authors.lastname: Jiang
authors.affiliation: Department of Critical Care Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
authors.forename: Tamil
authors.initials: T
authors.lastname: Anthonymuthu
authors.affiliation: Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
authors.forename: Dariush
authors.initials: D
authors.lastname: Mohammadyani
authors.affiliation: Department of Critical Care Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
authors.forename: Qin
authors.initials: Q
authors.lastname: Yang
authors.affiliation: Institute of Developmental Genetics, Helmholtz Zentrum München, Neuherberg, Germany.
authors.forename: Bettina
authors.initials: B
authors.lastname: Proneth
authors.affiliation: Division of Metabolic and Vascular Health, University of Warwick, Coventry, UK.
authors.forename: Judith
authors.identifier: http://orcid.org/0000-0002-4892-6828
authors.initials: J
authors.lastname: Klein-Seetharaman
authors.affiliation: Department of Cell Biology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
authors.forename: Simon
authors.initials: S
authors.lastname: Watkins
authors.affiliation: Department of Computational and Systems Biology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
authors.forename: Ivet
authors.initials: I
authors.lastname: Bahar
authors.affiliation: Department of Radiation Oncology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
authors.forename: Joel
authors.initials: J
authors.lastname: Greenberger
authors.affiliation: Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
authors.forename: Rama K
authors.initials: RK
authors.lastname: Mallampalli
authors.affiliation: Department of Biological Sciences, Columbia University, New York, New York, USA.|Department of Chemistry, Columbia University, New York, New York, USA.
authors.forename: Brent R
authors.identifier: http://orcid.org/0000-0002-3532-3868
authors.initials: BR
authors.lastname: Stockwell
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 Developmental Genetics, Helmholtz Zentrum München, Neuherberg, Germany.
authors.forename: Marcus
authors.initials: M
authors.lastname: Conrad
authors.affiliation: Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.|Department of Critical Care Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
authors.forename: Hülya
authors.initials: H
authors.lastname: Bayır
mesh_terms: D000818:Animals; D016718:Arachidonic Acid / Q000037:antagonists & inhibitors / Q000378:metabolism*; D016923:Cell Death / Q000187:drug effects; D002460:Cell Line; D003066:Coenzyme A Ligases / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000378:metabolism; D005231:Fatty Acids, Unsaturated / Q000037:antagonists & inhibitors / Q000378:metabolism*; D005260:Female; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010743:Phospholipids / Q000378:metabolism*
chemical_list: D005231:Fatty Acids, Unsaturated; D010743:Phospholipids; C011395:adrenic acid; D016718:Arachidonic Acid; C581020:Acsl4 protein, mouse; D003066:Coenzyme A Ligases