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von Mässenhausen, A.* ; Zamora Gonzalez, N.* ; 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.*

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

Sci. Adv. 8:eabl8920 (2022)
Postprint Forschungsdaten DOI PMC
Open Access Gold
Creative Commons Lizenzvertrag
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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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Korrespondenzautor
Schlagwörter Site-directed Mutagenesis; Renal Dipeptidase; Heme Oxygenase-1; Cell-death; Kidney; Degradation; Induction; Residues; Protects; Features
ISSN (print) / ISBN 2375-2548
e-ISSN 2375-2548
Zeitschrift Science Advances
Quellenangaben Band: 8, Heft: 5, Seiten: , Artikelnummer: eabl8920 Supplement: ,
Verlag American Association for the Advancement of Science (AAAS)
Verlagsort Washington, DC [u.a.]
Nichtpatentliteratur Publikationen
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Pancreatic Islet Research (IPI)
Förderungen Technische Universität Dresden
Sander-Stiftung
Else Kroner-Fresenius Stiftung
State of Saxony
Deutsche Forschungsgemeinschaft
European Fund for Regional Development-EFRE