2. Academic Validation
  3. FINO2 initiates ferroptosis through GPX4 inactivation and iron oxidation

FINO2 initiates ferroptosis through GPX4 inactivation and iron oxidation

  • Nat Chem Biol. 2018 May;14(5):507-515. doi: 10.1038/s41589-018-0031-6.
Michael M Gaschler 1,  Alexander A Andia 2,  Hengrui Liu 1,  Joleen M Csuka 3,  Brisa Hurlocker 2,  Christopher A Vaiana 2,  Daniel W Heindel 2,  Dylan S Zuckerman 2,  Pieter H Bos 3,  Eduard Reznik 3,  Ling F Ye 3,  Yulia Y Tyurina 4,  Annie J Lin 3,  Mikhail S Shchepinov 5,  Amy Y Chan 2,  Eveliz Peguero-Pereira 2,  Maksim A Fomich 6,  Jacob D Daniels 7,  Andrei V Bekish 8,  Vadim V Shmanai 6,  Valerian E Kagan 4,  Lara K Mahal 2,  K A Woerpel 9,  Brent R Stockwell 10 11
Affiliations

Affiliations

  • 1 Department of Chemistry, Columbia University, New York, NY, USA.
  • 2 Department of Chemistry, New York University, New York, NY, USA.
  • 3 Department of Biological Sciences, Columbia University, New York, NY, USA.
  • 4 Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, PA, USA.
  • 5 Retrotope Inc, Los Altos, CA, USA.
  • 6 Institute of Physical Organic Chemistry, National Academy of Sciences of Belarus, Minsk, Belarus.
  • 7 Department of Pharmacology, Columbia University, New York, NY, USA.
  • 8 Department of Chemistry, Belarusian State University, Minsk, Belarus.
  • 9 Department of Chemistry, New York University, New York, NY, USA. kwoerpel@nyu.edu.
  • 10 Department of Chemistry, Columbia University, New York, NY, USA. bstockwell@columbia.edu.
  • 11 Department of Biological Sciences, Columbia University, New York, NY, USA. bstockwell@columbia.edu.
PMID: 29610484 DOI: 10.1038/s41589-018-0031-6
Abstract

Ferroptosis is a non-apoptotic form of regulated cell death caused by the failure of the glutathione-dependent lipid-peroxide-scavenging network. FINO2 is an endoperoxide-containing 1,2-dioxolane that can initiate Ferroptosis selectively in engineered Cancer cells. We investigated the mechanism and structural features necessary for Ferroptosis initiation by FINO2. We found that FINO2 requires both an endoperoxide moiety and a nearby hydroxyl head group to initiate Ferroptosis. In contrast to previously described Ferroptosis inducers, FINO2 does not inhibit system xc- or directly target the reducing Enzyme GPX4, as do erastin and RSL3, respectively, nor does it deplete GPX4 protein, as does FIN56. Instead, FINO2 both indirectly inhibits GPX4 enzymatic function and directly oxidizes iron, ultimately causing widespread lipid peroxidation. These findings suggest that endoperoxides such as FINO2 can initiate a multipronged mechanism of Ferroptosis.

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