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Rajeeth, K.* ; Roessing, M.* ; Lehners, M.* ; Dietz, L.* ; Schmitt, A.* ; Hailfinger, S.* ; Peter, A. ; Quintanilla-Martinez, L.* ; Gonzalez-Menendez, I.* ; Mederacke, I.* ; Ott, G.* ; Sandner, P.* ; Schwab, M.* ; Feil, R.* ; Feil, S.*

Pharmacological activation of NO-cGMP signalling attenuates metabolic dysfunction-associated steatohepatitis.

Br. J. Pharmacol., DOI: 10.1111/bph.70523 (2026)
Verlagsversion DOI
Open Access Hybrid
Creative Commons Lizenzvertrag
Background and Purpose: Metabolic dysfunction-associated steatohepatitis (MASH) is linked to activation of hepatic stellate cells (HSCs) to α-smooth muscle actin–positive myofibroblasts that produce collagen and proinflammatory cytokines. Quiescent HSCs express the NO-cGMP signalling axis. Modulating this pathway could alter HSC activation and fibrosis during MASH progression. Experimental Approach: Using transgenic cGMP sensor mice, we monitored NO-induced cGMP in living HSCs. The relevance of this pathway was analyzed using HSC-specific mouse models, ApoE-deficient mice on high-fat diet as a MASH model, human liver sections, and published scRNA-seq datasets. For pharmacological activation of NO-cGMP signalling, BAY-543, an activator of NO-sensitive guanylyl cyclase (NO-GC) was used. Key Results: HSCs in primary culture and liver tissue generated NO-induced cGMP and expressed NO-GC and cGMP-dependent protein kinase type I (cGKI). Compared to controls, HSC-specific cGKI knockout livers showed enhanced myofibroblast marker expression, indicating increased HSC activation and MASH susceptibility. MASH mice developed steatosis, fibrosis, and inflammation, and showed a high number of HSCs expressing NO-GC and cGKI. cGKI expression was also increased in human fibrotic livers as compared to healthy tissue. In MASH livers, oxidative stress could lead to reduced sensitivity of NO-GC to NO. Treatment of MASH mice with BAY-543, which targets oxidized/NO-insensitive NO-GC, significantly attenuated HSC activation, inflammation, collagen deposition, macro-steatosis, fibrosis, and serum liver enzymes. Conclusion and Implications: The NO-cGMP-cGKI axis serves as both a functional pathway marker and regulator of HSCs. Pharmacological elevation of cGMP with an NO-GC activator represents a promising therapeutic strategy for MASH.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter Cgmp Signalling ; Fret Imaging ; Gucy ; Hepatic Stellate Cells ; Liver Fibrosis ; Mash ; No-gc Activator ; Prkg1; Dependent Protein-kinase; Soluble Guanylate-cyclase; Hepatic Stellate Cells; Nitric-oxide; Concise Guide; Portal-hypertension; Mice; Mechanisms; Cirrhosis; Adhesion
ISSN (print) / ISBN 0007-1188
e-ISSN 1476-5381
Zeitschrift British Journal of Pharmacology
Verlag Wiley
Verlagsort 111 River St, Hoboken 07030-5774, Nj Usa
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Diabetes Research and Metabolic Diseases (IDM)
Förderungen Reinhard Frank Stiftung
Robert Bosch Stiftung
Dr. K.H. Eberle Stiftung
Horizon 2020 Framework Programme
EU Framework Program for Research and Innovation "Horizon 2020"-ERA-CVD JTC2017-044
Deutsche Forschungsgemeinschaft