GPX4 Is a Key Regulator of Ferroptosis

Ferroptosis is a form of nonapoptotic cell death involving the iron-dependent production of reactive oxygen species (ROS). Several small molecules that selectively induce ferroptosis in oncogenic RAS (RAS^V12)-expressing cells have been described, but whether these compounds target a common regulatory pathway is unclear. Yang and colleagues found that erastin, a ferroptosis-inducing compound, caused glutathione depletion, which was necessary for selective lethality of erastin and erastin-induced generation of cytosolic and lipid ROS in RAS^V12-expressing cells. The depletion of glutathione in erastin-treated cells inactivated glutathione-dependent peroxidases (GPX), which catalyze the reduction of hydrogen peroxide and organic hydroperoxides and require glutathione as a cofactor. Because RSL3, another ferroptosis-inducing compound, increased lipid ROS production in the absence of glutathione depletion, a chemoproteomic approach was used to identify RSL3 targets in RAS^V12-expressing cells. RSL3 was found to bind GPX4 and inactivate its peroxidase activity, and knockdown of GPX4 induced selective ferroptotic cell death of RAS^V12-expressing cells, indicating that GPX4 is a central regulator of both erastin- and RSL3-induced ferroptosis. Consistent with these findings, 10 additional structurally diverse compounds exhibiting RAS^V12-selective ferroptosis were identified and found to similarly inhibit GPX4 and induce lipid ROS accumulation, further indicating that modulation of GPX4 is a common mechanism shared by ferroptosis-inducing small molecules. Moreover, both RSL3 and erastin induced ferroptosis in vivo in xenograft mouse tumor models driven by oncogenic RAS. Of note, sensitivity profiling across a panel of cancer cell lines identified diffuse large B-cell lymphomas (DLBCL) and renal cell carcinomas (RCC) as being particularly ferroptosis sensitive. Erastin induced lipid ROS generation in both DLBCL and RCC cells, and knockdown of GPX4 alone was sufficient to induce ferroptosis of RCC cells. Together, these findings identify GPX4 as an essential regulator of ferroptosis and suggest that ferroptosis-inducing compounds may have therapeutic applications in diverse cancer types.

Yang WS, SriRamaratnam R, Welsch ME, Shimada K, Skouta R, Viswanathan VS, et al. Regulation of ferroptotic cell death by GPX4. Cell 2014;156:317–31.

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