2. Academic Validation
  3. Ferroptotic cell death triggered by conjugated linolenic acids is mediated by ACSL1

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

  • Nat Commun. 2021 Apr 14;12(1):2244. doi: 10.1038/s41467-021-22471-y.
Alexander Beatty 1,  Tanu Singh 2,  Yulia Y Tyurina 3 4,  Vladimir A Tyurin 3 4,  Svetlana Samovich 3 4,  Emmanuelle Nicolas 2,  Kristen Maslar 5,  Yan Zhou 2,  Kathy Q Cai 2,  Yinfei Tan 2,  Sebastian Doll 6,  Marcus Conrad 6 7,  Aravind Subramanian 8,  Hülya Bayır 3 4 9,  Valerian E Kagan 3 4 10 11 12 13,  Ulrike Rennefahrt 14,  Jeffrey R Peterson 15
Affiliations

Affiliations

  • 1 Fox Chase Cancer Center, Philadelphia, Pennsylvania, USA. [email protected].
  • 2 Fox Chase Cancer Center, Philadelphia, Pennsylvania, USA.
  • 3 Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, PA, USA.
  • 4 Center for Free Radical and Antioxidant Health, University of Pittsburgh, Pittsburgh, PA, USA.
  • 5 Department of Biochemistry and Molecular Biology, Drexel University College of Medicine, Philadelphia, PA, USA.
  • 6 Institute of Metabolism and Cell Death, Helmholtz Zentrum München, Neuherberg, Germany.
  • 7 National Research Medical University, Laboratory of Experimental Oncology, Ostrovityanova 1, Moscow, 117997, Russia.
  • 8 Broad Institute of Harvard and MIT, Cambridge, MA, USA.
  • 9 Department of Critical Care Medicine, Safar Center for Resuscitation Research, University of Pittsburgh, Pittsburgh, PA, USA.
  • 10 Department of Chemistry, University of Pittsburgh, Pittsburgh, PA, USA.
  • 11 Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA, USA.
  • 12 Department of Radiation Oncology, University of Pittsburgh, Pittsburgh, PA, USA.
  • 13 Laboratory of Navigational Redox Lipidomics, IM Sechenov Moscow State Medical University, Moscow, Russia.
  • 14 Metanomics Health GmbH, Berlin, Germany.
  • 15 Fox Chase Cancer Center, Philadelphia, Pennsylvania, USA. [email protected].
PMID: 33854057 DOI: 10.1038/s41467-021-22471-y
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.

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