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

Alexander Beatty (), Tanu Singh, Yulia Y. Tyurina, Vladimir A. Tyurin, Svetlana Samovich, Emmanuelle Nicolas, Kristen Maslar, Yan Zhou, Kathy Q. Cai, Yinfei Tan, Sebastian Doll, Marcus Conrad, Aravind Subramanian, Hülya Bayır, Valerian E. Kagan, Ulrike Rennefahrt and Jeffrey R. Peterson ()
Additional contact information
Alexander Beatty: Fox Chase Cancer Center
Tanu Singh: Fox Chase Cancer Center
Yulia Y. Tyurina: University of Pittsburgh
Vladimir A. Tyurin: University of Pittsburgh
Svetlana Samovich: University of Pittsburgh
Emmanuelle Nicolas: Fox Chase Cancer Center
Kristen Maslar: Drexel University College of Medicine
Yan Zhou: Fox Chase Cancer Center
Kathy Q. Cai: Fox Chase Cancer Center
Yinfei Tan: Fox Chase Cancer Center
Sebastian Doll: Helmholtz Zentrum München
Marcus Conrad: Helmholtz Zentrum München
Aravind Subramanian: Broad Institute of Harvard and MIT
Hülya Bayır: University of Pittsburgh
Valerian E. Kagan: University of Pittsburgh
Ulrike Rennefahrt: Metanomics Health GmbH
Jeffrey R. Peterson: Fox Chase Cancer Center

Nature Communications, 2021, vol. 12, issue 1, 1-18

Abstract: Abstract 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.

Date: 2021
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DOI: 10.1038/s41467-021-22471-y

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