Pharmacological activation of NO‐cGMP signalling attenuates metabolic dysfunction‐associated steatohepatitis
Krithika Rajeeth, Malte Roessing, Moritz Lehners, Lisa Dietz, Anja Schmitt, Stephan Hailfinger, Andreas Peter, Leticia Quintanilla‐Martinez, Irene Gonzalez‐Menendez, Ingmar Mederacke, German Ott, Peter Sandner, Matthias Schwab, Robert Feil, Susanne FeilBackground 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.