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

TLDR

System x_c^− mediates cystine–glutamate exchange and is linked to many diseases, yet potent pharmacological inhibitors have been difficult to develop. This study demonstrates that erastin is a potent, selective inhibitor of system x_c^−. Inhibition of system x_c^− by erastin or the approved drug sorafenib activates ER‑stress signaling, upregulates CHAC1 as a pharmacodynamic marker, induces ferroptosis, and is associated with distinct metabolic changes in patients, while genetic screens reveal novel genes upregulated in ferroptosis‑resistant cells.

Abstract

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.