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

Elife. 2014 May 20:3:e02523. doi: 10.7554/eLife.02523.


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 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.DOI:

Keywords: SLC7A11; cell death; cystine; erastin; reactive oxygen species; sorafenib.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 20-Hydroxysteroid Dehydrogenases / metabolism
  • Amino Acid Transport System y+ / antagonists & inhibitors
  • Amino Acid Transport System y+ / metabolism
  • Apoptosis* / drug effects
  • Biomarkers / metabolism
  • Cell Line
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cell Separation
  • Cystine / metabolism*
  • Endoplasmic Reticulum Stress* / drug effects
  • Glutamic Acid / metabolism*
  • Humans
  • Iron / pharmacology
  • Niacinamide / adverse effects
  • Niacinamide / analogs & derivatives
  • Niacinamide / pharmacology
  • Phenylurea Compounds / adverse effects
  • Phenylurea Compounds / pharmacology
  • Piperazines / chemistry
  • Piperazines / pharmacology
  • Protein Kinase Inhibitors / pharmacology
  • Sequence Analysis, RNA
  • Sorafenib
  • Structure-Activity Relationship
  • Transcriptome / drug effects
  • Up-Regulation / drug effects


  • Amino Acid Transport System y+
  • Biomarkers
  • Phenylurea Compounds
  • Piperazines
  • Protein Kinase Inhibitors
  • erastin
  • Niacinamide
  • Glutamic Acid
  • Cystine
  • Sorafenib
  • Iron
  • 20-Hydroxysteroid Dehydrogenases