Dexamethasone sensitizes to ferroptosis by glucocorticoid receptor-induced dipeptidase-1 expression and glutathione depletion
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, an...
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sg-ntu-dr.10356-1643712023-03-05T16:54:02Z Dexamethasone sensitizes to ferroptosis by glucocorticoid receptor-induced dipeptidase-1 expression and glutathione depletion 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 Lee Kong Chian School of Medicine (LKCMedicine) Science::Medicine Dexamethasones Glucocorticoid Receptor 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. Published version 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. 2023-01-18T02:19:55Z 2023-01-18T02:19:55Z 2022 Journal Article 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-. https://dx.doi.org/10.1126/sciadv.abl8920 2375-2548 https://hdl.handle.net/10356/164371 10.1126/sciadv.abl8920 35108055 2-s2.0-85123974058 5 8 eabl8920 en Science Advances © 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). application/pdf |
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Science::Medicine Dexamethasones Glucocorticoid Receptor 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 Dexamethasone sensitizes to ferroptosis by glucocorticoid receptor-induced dipeptidase-1 expression and glutathione depletion |
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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. |
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Lee Kong Chian School of Medicine (LKCMedicine) |
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Lee Kong Chian School of Medicine (LKCMedicine) 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 |
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Article |
author |
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 |
author_sort |
von Mässenhausen, Anne |
title |
Dexamethasone sensitizes to ferroptosis by glucocorticoid receptor-induced dipeptidase-1 expression and glutathione depletion |
title_short |
Dexamethasone sensitizes to ferroptosis by glucocorticoid receptor-induced dipeptidase-1 expression and glutathione depletion |
title_full |
Dexamethasone sensitizes to ferroptosis by glucocorticoid receptor-induced dipeptidase-1 expression and glutathione depletion |
title_fullStr |
Dexamethasone sensitizes to ferroptosis by glucocorticoid receptor-induced dipeptidase-1 expression and glutathione depletion |
title_full_unstemmed |
Dexamethasone sensitizes to ferroptosis by glucocorticoid receptor-induced dipeptidase-1 expression and glutathione depletion |
title_sort |
dexamethasone sensitizes to ferroptosis by glucocorticoid receptor-induced dipeptidase-1 expression and glutathione depletion |
publishDate |
2023 |
url |
https://hdl.handle.net/10356/164371 |
_version_ |
1759857520611950592 |