Metabolic dysfunction-associated steatotic liver disease (MASLD) is characterized by progressive fibrosis and an increased risk of hepatocellular carcinoma (HCC). Recently, approved drug treatments for MASLD, including thyroid hormone receptor beta (THR-β) and glucagon-like peptide-1 (GLP-1) receptor agonists, have been effective in treating the underlying metabolic causes of MASLD. However, more effective and acute treatments, particularly for already advanced or cirrhotic steatohepatitis, remain elusive. Other drug candidates, such as cyclophilin inhibitors, which have shown promise for treating advanced MASLD, are still under investigation. Because advanced MASLD reflects both upstream metabolic stress and downstream, self-sustaining injury responses promoting inflammation and fibrogenesis, we investigated whether pairing GLP-1 agonism (metabolic correction) with cyclophilin inhibition (fibrosis and inflammation remodeling) would yield additive or emergent benefits. Thus, we evaluated Semaglutide, Rencofilstat (CRV431), and their co-administration in a C57BL/6J model of diet- and toxin-induced MASLD via a Western diet, sucrose supplementation, and chronic carbon tetrachloride exposure. Semaglutide monotherapy significantly reduced body weight and decreased HCC burden (Kruskal-Wallis Analysis, p < 0.0001) whereas fibrosis quantified by picrosirius red staining did not differ significantly across the treatment groups (Welch's Analysis of Variance, p = 0.1725). Co-therapy did not improve collagen deposition compared with monotherapy. These findings indicate that the combination of GLP-1 receptor agonism with cyclophilin inhibition does not confer additive antifibrotic benefits in this advanced MASLD model, underscoring stage-dependent constraints on therapeutic synergy.
