This study investigates the pharmacological inhibition of cystine-glutamate exchange by the antiporter system x_c-. The compound erastin is identified as a potent and selective inhibitor of this system, leading to the induction of ferroptosis, a form of iron-dependent cell death. The authors also find that the clinically approved anti-cancer drug sorafenib can inhibit system x_c- and trigger ferroptosis under certain conditions. They further demonstrate that small molecule inhibition of system x_c- function results in endoplasmic reticulum (ER) stress, as indicated by the upregulation of ER stress response genes, particularly CHAC1. Additionally, they identify new genes that are upregulated in cells resistant to ferroptosis, which may play a role in the detoxification of oxidative lipid breakdown products. The study provides insights into the mechanisms of action of erastin and sorafenib, and suggests potential therapeutic applications in cancer and other diseases.This study investigates the pharmacological inhibition of cystine-glutamate exchange by the antiporter system x_c-. The compound erastin is identified as a potent and selective inhibitor of this system, leading to the induction of ferroptosis, a form of iron-dependent cell death. The authors also find that the clinically approved anti-cancer drug sorafenib can inhibit system x_c- and trigger ferroptosis under certain conditions. They further demonstrate that small molecule inhibition of system x_c- function results in endoplasmic reticulum (ER) stress, as indicated by the upregulation of ER stress response genes, particularly CHAC1. Additionally, they identify new genes that are upregulated in cells resistant to ferroptosis, which may play a role in the detoxification of oxidative lipid breakdown products. The study provides insights into the mechanisms of action of erastin and sorafenib, and suggests potential therapeutic applications in cancer and other diseases.