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Title: Dexamethasone sensitizes to ferroptosis by glucocorticoid receptor-induced dipeptidase-1 expression and glutathione depletion
Authors: von Mässenhausen, Anne
Gonzalez, Nadia Zamora
Maremonti, Francesca
Belavgeni, Alexia
Tonnus, Wulf
Meyer, Claudia
Beer, Kristina
Hannani, Monica T.
Lau, Arthur
Peitzsch, Mirko
Hoppenz, Paul
Locke, Sophie
Chavakis, Triantafyllos
Kramann, Rafael
Muruve, Daniel A.
Hugo, Christian
Bornstein, Stefan R.
Linkermann, Andreas
Keywords: Science::Medicine
Issue Date: 2022
Source: von Mässenhausen, A., Gonzalez, N. Z., Maremonti, F., Belavgeni, A., Tonnus, W., Meyer, C., Beer, K., Hannani, M. T., Lau, A., Peitzsch, M., Hoppenz, P., Locke, S., Chavakis, T., Kramann, R., Muruve, D. A., Hugo, C., Bornstein, S. R. & Linkermann, A. (2022). Dexamethasone sensitizes to ferroptosis by glucocorticoid receptor-induced dipeptidase-1 expression and glutathione depletion. Science Advances, 8(5), eabl8920-.
Journal: Science Advances 
Abstract: 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.
ISSN: 2375-2548
DOI: 10.1126/sciadv.abl8920
Schools: Lee Kong Chian School of Medicine (LKCMedicine) 
Rights: © 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).
Fulltext Permission: open
Fulltext Availability: With Fulltext
Appears in Collections:LKCMedicine Journal Articles

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