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. Epub 2018 Apr 2.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis*
  • Carbolines / chemistry
  • Cell Line, Tumor
  • Colorimetry
  • Dioxolanes / chemistry
  • Endoplasmic Reticulum / metabolism
  • Glutathione / chemistry
  • Glutathione Peroxidase / chemistry
  • Glutathione Peroxidase / physiology*
  • Homeostasis
  • Humans
  • Iron / chemistry*
  • Lipid Peroxidation
  • Mice
  • Microsomes / metabolism
  • NADP / chemistry
  • Oxidative Stress
  • Phospholipid Hydroperoxide Glutathione Peroxidase
  • Piperazines / chemistry
  • Protein Engineering
  • Structure-Activity Relationship


  • Carbolines
  • Dioxolanes
  • Piperazines
  • RSL3 compound
  • erastin
  • NADP
  • Iron
  • Phospholipid Hydroperoxide Glutathione Peroxidase
  • Glutathione Peroxidase
  • Glutathione
  • formal glycol