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.
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We would like to thank R. Opitz, C. Laqua, and A. Pioch for expert technical assistance, M. Langner for expert help with mass spectrometry, and the Light Microscopy Facility at Dresden BIOTEC, in particular H. Hartmann and E. Geibelt, for the expert help. We thank the Microstructure Facility of the BIOTEC at Technische Universitat Dresden [partly funded by the State of Saxony and the European Fund for Regional Development-EFRE (100344812)]. Work in the Linkermann laboratory is funded by the SFB-TRR 205, SFB-TRR 127, and the international research training group (IRTG) 2251. This work was additionally supported by the German Research Foundation (DFG), priority program on ferroptosis (SPP2306) to A.v.M. and A.L., the Heisenberg-Professorship to A.L. (project number 324141047), and an instrument grant support to M.P. (INST 515/28-1 FUGG). We further thank the Else Kr?ner-Fresenius Stiftung and the Sander-Stiftung for supporting our laboratory.
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