Pharmacological inhibition of cystine–glutamate exchange induces endoplasmic reticulum stress and ferroptosis

Exchange of extracellular cystine for intracellular glutamate by the antiporter system x c − is implicated in numerous pathologies. Pharmacological agents that inhibit system x c − activity with high potency have long been sought, but have remained elusive. In this study, we report that the small molecule erastin is a potent, selective inhibitor of system x c − . RNA sequencing revealed that inhibition of cystine–glutamate exchange leads to activation of an ER stress response and upregulation of CHAC1 , providing a pharmacodynamic marker for system x c − inhibition. We also found that the clinically approved anti-cancer drug sorafenib, but not other kinase inhibitors, inhibits system x c − function and can trigger ER stress and ferroptosis. In an analysis of hospital records and adverse event reports, we found that patients treated with sorafenib exhibited unique metabolic and phenotypic alterations compared to patients treated with other kinase-inhibiting drugs. Finally, using a genetic approach, we identified new genes dramatically upregulated in cells resistant to ferroptosis.