GTX-11 improves portal hypertension, liver fibrosis, and sinusoidal cells phenotype in experimental MASH

Abstract

Background & Aims

Steatotic liver disease can lead to the development of metabolic dysfunction-associated steatohepatitis (MASH), the prevalence of which is rapidly increasing, intensifying the need to find an effective treatment. GTX-11 is a first-in-class drug with anti-inflammatory and antifibrotic properties mediated by the modulation of the transforming growth factor beta pathway. The present study evaluated the effects of GTX-11 on hepatic hemodynamics and liver fibrosis, as well as its underlying mechanisms, in a preclinical model of MASH, and in human precision-cut liver slices (hPCLS).

Methods

Male Wistar MASH rats received GTX-11 (1 and 10 mg/kg/day) or vehicle, for 14 days (n = 15/group). In vivo systemic and hepatic hemodynamics, fibrosis, biochemical parameters, and hepatic cells phenotype were analyzed. hPCLS were obtained from human hepatic resections and incubated with the active metabolite of GTX-11 (GTX-11m) (1 μM or 10 μM) or vehicle for 24 h. Gene expression changes were evaluated by RNA sequencing and gene deconvolution analysis was performed (n = 6/group).

Results

MASH rats receiving GTX-11 showed a significant dose-dependent reduction in portal pressure compared with the vehicle (-8.4% p = 0.05 and -11.7% p <0.01 for 1 and 10 mg/kg, respectively), associated with lower hepatic fibrosis at 10 mg/kg (-28%, p <0.01). At the cellular level, GTX-11-treated rats showed hepatic stellate cells (HSCs) deactivation and endothelial cells redifferentiation. Transcriptomic analysis from hPCLS revealed that GTX-11m promoted HSCs deactivation and inhibition of pro-fibrogenic pathways, as well as extracellular matrix remodeling. Gene deconvolution analysis confirmed the beneficial effects of GTX-11m on HSCs, promoting their deactivation and rebalance.

Conclusions

This study demonstrates for the first time the beneficial effects of GTX-11 on portal hypertension and liver fibrosis in MASH by means of HSCs deactivation and endothelial phenotype restoration. Validation in human liver tissues encourages its clinical evaluation as a possible new treatment for this disease.

Impact and implications

Metabolic dysfunction-associated steatohepatitis (MASH) affects >3–6% of the world’s population, and this number continues to increase. Despite its high prevalence, there is currently no specific, generally effective, and safe treatment for the disease. This study demonstrates, for the first time, the therapeutic potential of GTX-11 in treating fibrosis and portal hypertension associated with MASH by deactivating hepatic stellate cells and enhancing endothelial phenotype. These findings highlight GTX-11 as a promising candidate for future therapeutic strategies aimed at reversing liver fibrosis and improving patient outcomes in MASH.