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

Exchange of extracellular cystine for intracellular glutamate by the antiporter system xc (-) is implicated in numerous pathologies. Pharmacological agents that inhibit system xc (-) 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 xc (-). 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 xc (-) inhibition. We also found that the clinically approved anti-cancer drug sorafenib, but not other kinase inhibitors, inhibits system xc (-) function and can…

• HH
  Howard Hughes Medical Institute
• NI
  National Institutes of Health

  Awards: 1K99CA166517-01, 5R01CA097061, 5R01GM085081 and R01CA161061