Work

Pharmacological activation of NO‐cGMP signalling attenuates metabolic dysfunction‐associated steatohepatitis

Year: 2026

Type: article

Abstract: 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.

Source: British Journal of Pharmacology

DOI: 10.1111/bph.70523