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

Emmanuelle Nicolas, Yan Zhou, Alexander Beatty, Tanu Singh, Yulia Y. Tyurina, Svetlana Samovich, Kristen Maslar, Kathy Cai, Yinfei Tan, Sebastian Doll, Marcus Conrad, Aravind Subramanian, Hülya Bayır, Valerian E. Kagan, Ulrike Rennefahrt, J. R. Peterson

Research output: Contribution to journalArticlepeer-review

113 Scopus citations

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.

Original languageEnglish
Article number2244
Pages (from-to)2244
JournalNature Communications
Volume12
Issue number1
DOIs
StatePublished - Mar 14 2021

Keywords

  • Animals
  • Cell Death
  • Coenzyme A Ligases/genetics
  • Ferroptosis
  • Humans
  • Linolenic Acids/metabolism
  • Mice
  • Mice, Inbred NOD
  • Phospholipid Hydroperoxide Glutathione Peroxidase/genetics
  • Triple Negative Breast Neoplasms/enzymology

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