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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
Schlagwörter Site-directed Mutagenesis; Renal Dipeptidase; Heme Oxygenase-1; Cell-death; Kidney; Degradation; Induction; Residues; Protects; Features
Sprache englisch
Veröffentlichungsjahr 2022
HGF-Berichtsjahr 2022
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.]
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Pancreatic Islet Research (IPI)
POF Topic(s) 90000 - German Center for Diabetes Research
Forschungsfeld(er) Helmholtz Diabetes Center
PSP-Element(e) G-502600-007
Förderungen Technische Universität Dresden
Sander-Stiftung
Else Kroner-Fresenius Stiftung
State of Saxony
Deutsche Forschungsgemeinschaft
European Fund for Regional Development-EFRE
DOI 10.1126/sciadv.abl8920
WOS ID WOS:000750618100015
Scopus ID 85123974058
PubMed ID 35108055
Erfassungsdatum 2022-04-29
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