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Beatty A , Singh T , Tyurina YY , Tyurin VA , Samovich S , Nicolas E , Maslar K , Zhou Y , Cai KQ , Tan Y , Doll S , Conrad M , Subramanian A , Bayır H , Kagan VE , Rennefahrt U , Peterson JR
Ferroptotic cell death triggered by conjugated linolenic acids is mediated by ACSL1
Nat Commun. 2021 Apr 14;12(1) :2244
PMID: 33854057   
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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.
2041-1723 Beatty, Alexander Orcid: 0000-0002-6054-4064 Singh, Tanu Tyurina, Yulia Y Tyurin, Vladimir A Samovich, Svetlana Nicolas, Emmanuelle Maslar, Kristen Orcid: 0000-0002-9153-3122 Zhou, Yan Cai, Kathy Q Tan, Yinfei Doll, Sebastian Conrad, Marcus Orcid: 0000-0003-1140-5612 Subramanian, Aravind Bayır, Hülya Orcid: 0000-0003-2361-4120 Kagan, Valerian E Orcid: 0000-0002-7245-1885 Rennefahrt, Ulrike Peterson, Jeffrey R Orcid: 0000-0002-0604-718x U19 AI068021/AI/NIAID NIH HHS/United States P30 CA006927/CA/NCI NIH HHS/United States Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S. Nat Commun. 2021 Apr 14;12(1):2244. doi: 10.1038/s41467-021-22471-y.