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

Anne von Mässenhausen, Nadia Zamora Gonzalez, Francesca Maremonti, Alexia Belavgeni, Wulf Tonnus, Claudia Meyer, Kristina Beer, Monica T. Hannani, Arthur Lau, Mirko Peitzsch, Paul Hoppenz, Sophie Locke, Triantafyllos Chavakis, Rafael Kramann, Daniel A. Muruve, Christian Hugo, Stefan R. Bornstein, Andreas Linkermann*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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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.

Original languageEnglish
Article numbereabl8920
JournalScience advances
Issue number5
Publication statusPublished - 2 Feb 2022

Bibliographical note

Funding Information:
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 Kröner-Fresenius Stiftung and the Sander-Stiftung for supporting our laboratory.

Publisher Copyright:
© 2022 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution License 4.0 (CC BY).


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