Cell
Volume 156, Issues 1–2, 16 January 2014, Pages 317-331
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Article
Regulation of Ferroptotic Cancer Cell Death by GPX4

https://doi.org/10.1016/j.cell.2013.12.010Get rights and content
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Highlights

  • Metabolomic profiling revealed GSH depletion as one mechanism of ferroptosis

  • Chemoproteomics identified GPX4 as a target for RSL3, a second ferroptosis inducer

  • GPX4 is a central regulator of ferroptosis, akin to bcl-2 in apoptosis

  • DLBCLs and renal cell carcinomas are sensitive to ferroptotic cell death

Summary

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.

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These authors contributed equally to this work