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Beatty, A.* ; Singh, T.* ; Tyurina, Y.Y.* ; Tyurin, V.A.* ; Samovich, S.* ; Nicolas, E.* ; Maslar, K.* ; Zhou, Y.* ; Cai, K.Q.* ; Tan, Y.* ; Doll, S. ; Conrad, M. ; Subramanian, A.* ; Bayir, H.* ; Rennefahrt, U.* ; Peterson, J.R.*

Ferroptotic cell death triggered by conjugated linolenic acids is mediated by ACSL1.

Nat. Commun. 12:2244 (2021)
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Ferroptosis is associated with lipid hydroperoxides generated by the oxidation of polyunsaturated acyl chains. Lipid hydroperoxides are reduced by glutathione peroxidase 4 (GPX4) and GPX4 inhibitors induce ferroptosis. However, the therapeutic potential of triggering ferroptosis in cancer cells with polyunsaturated fatty acids is unknown. Here, we identify conjugated linoleates including α-eleostearic acid (αESA) as ferroptosis inducers. αESA does not alter GPX4 activity but is incorporated into cellular lipids and promotes lipid peroxidation and cell death in diverse cancer cell types. αESA-triggered death is mediated by acyl-CoA synthetase long-chain isoform 1, which promotes αESA incorporation into neutral lipids including triacylglycerols. Interfering with triacylglycerol biosynthesis suppresses ferroptosis triggered by αESA but not by GPX4 inhibition. Oral administration of tung oil, naturally rich in αESA, to mice limits tumor growth and metastasis with transcriptional changes consistent with ferroptosis. Overall, these findings illuminate a potential approach to ferroptosis, complementary to GPX4 inhibition.
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Publication type Article: Journal article
Document type Scientific Article
Language english
Publication Year 2021
HGF-reported in Year 2021
ISSN (print) / ISBN 2041-1723
e-ISSN 2041-1723
Journal Nature Communications
Quellenangaben Volume: 12, Issue: 1, Pages: , Article Number: 2244 Supplement: ,
Publisher Nature Publishing Group
Publishing Place London
Reviewing status Peer reviewed
Institute(s) Institute of Metabolism and Cell Death (MCD)
POF-Topic(s) 30203 - Molecular Targets and Therapies
Research field(s) Genetics and Epidemiology
PSP Element(s) G-506900-001
Grants NCI NIH HHS
NIAID NIH HHS
DOI 10.1038/s41467-021-22471-y
WOS ID WOS:000640561300008
Scopus ID 85104482206
PubMed ID 33854057
Erfassungsdatum 2021-04-22
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