Regulation of ferroptotic cancer cell death by GPX4

Cell. 2014 Jan 16;156(1-2):317-331. doi: 10.1016/j.cell.2013.12.010.


Ferroptosis is a form of nonapoptotic cell death for which key regulators remain unknown. We sought a common mediator for the lethality of 12 ferroptosis-inducing small molecules. We used targeted metabolomic profiling to discover that depletion of glutathione causes inactivation of glutathione peroxidases (GPXs) in response to one class of compounds and a chemoproteomics strategy to discover that GPX4 is directly inhibited by a second class of compounds. GPX4 overexpression and knockdown modulated the lethality of 12 ferroptosis inducers, but not of 11 compounds with other lethal mechanisms. In addition, two representative ferroptosis inducers prevented tumor growth in xenograft mouse tumor models. Sensitivity profiling in 177 cancer cell lines revealed that diffuse large B cell lymphomas and renal cell carcinomas are particularly susceptible to GPX4-regulated ferroptosis. Thus, GPX4 is an essential regulator of ferroptotic cancer cell death.

Publication types

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

MeSH terms

  • Animals
  • Carbolines / pharmacology*
  • Carcinoma, Renal Cell / drug therapy
  • Cell Death / drug effects*
  • Cell Line, Tumor
  • Gene Knockdown Techniques
  • Glutathione / metabolism
  • Glutathione Peroxidase / antagonists & inhibitors*
  • Glutathione Peroxidase / genetics
  • Glutathione Peroxidase / metabolism
  • Heterografts
  • Humans
  • Lymphoma, B-Cell / drug therapy
  • Mice
  • Neoplasm Transplantation
  • Neoplasms / drug therapy
  • Phospholipid Hydroperoxide Glutathione Peroxidase
  • Piperazines / pharmacology*


  • Carbolines
  • Piperazines
  • RSL3 compound
  • erastin
  • Phospholipid Hydroperoxide Glutathione Peroxidase
  • Glutathione Peroxidase
  • Glutathione