Dexamethasone sensitizes to ferroptosis by glucocorticoid receptor-induced dipeptidase-1 expression and glutathione depletion

Sci Adv. 2022 Feb 4;8(5):eabl8920. doi: 10.1126/sciadv.abl8920. Epub 2022 Feb 2.


Dexamethasone is widely used as an immunosuppressive therapy and recently as COVID-19 treatment. Here, we demonstrate that dexamethasone sensitizes to ferroptosis, a form of iron-catalyzed necrosis, previously suggested to contribute to diseases such as acute kidney injury, myocardial infarction, and stroke, all of which are triggered by glutathione (GSH) depletion. GSH levels were significantly decreased by dexamethasone. Mechanistically, we identified that dexamethasone up-regulated the GSH metabolism regulating protein dipeptidase-1 (DPEP1) in a glucocorticoid receptor (GR)-dependent manner. DPEP1 knockdown reversed the phenotype of dexamethasone-induced ferroptosis sensitization. Ferroptosis inhibitors, the DPEP1 inhibitor cilastatin, or genetic DPEP1 inactivation reversed the dexamethasone-induced increase in tubular necrosis in freshly isolated renal tubules. Our data indicate that dexamethasone sensitizes to ferroptosis by a GR-mediated increase in DPEP1 expression and GSH depletion. Together, we identified a previously unknown mechanism of glucocorticoid-mediated sensitization to ferroptosis bearing clinical and therapeutic implications.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Carbolines / adverse effects
  • Carbolines / pharmacology
  • Cell Line
  • Dexamethasone / pharmacology*
  • Dipeptidases / genetics*
  • Dipeptidases / metabolism
  • Ferroptosis / drug effects*
  • Ferroptosis / genetics*
  • Fluorescent Antibody Technique
  • GPI-Linked Proteins / genetics
  • GPI-Linked Proteins / metabolism
  • Gene Expression Regulation / drug effects*
  • Gene Knockdown Techniques
  • Glutathione / metabolism*
  • Humans
  • Immunophenotyping
  • Oxidation-Reduction / drug effects
  • Piperazines / adverse effects
  • Piperazines / pharmacology
  • Receptors, Glucocorticoid / metabolism*


  • Carbolines
  • GPI-Linked Proteins
  • Piperazines
  • RSL3 compound
  • Receptors, Glucocorticoid
  • erastin
  • Dexamethasone
  • Dipeptidases
  • dipeptidase 1
  • Glutathione