GSK805 inhibits alpha‐smooth muscle expression and modulates liver inflammation without impairing the well‐being of mice

Abstract Cholestatic liver diseases, such as primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC), lead to inflammation and severe hepatic damage with limited therapeutic options. This study assessed the efficacy of the inverse RORγt agonist, GSK805, both in vitro using the hepatic stellate cell‐line LX‐2 and in vivo using male bile duct‐ligated BALB/c mice. In vitro, 0.3 μM GSK805 reduced alpha‐smooth muscle actin expression in LX‐2 cells. In vivo, GSK805 significantly decreased IL‐23R, TNF‐α, and IFN‐γ expression in cholestatic liver. Despite high concentrations of GSK805 in the liver, no significant reduction in fibrosis was noticed. GSK805 significantly increased aspartate aminotransferase and alanine aminotransferase activity in the blood, while levels of glutamate dehydrogenase, alkaline phosphatase, and bilirubin were not substantially increased. Importantly, GSK805 did neither increase an animal distress score nor substantially reduce body weight, burrowing activity, or nesting behavior. These results suggest that a high liver concentration of GSK805 is achieved by daily oral administration and that this drug modulates inflammation in cholestatic mice without impairing animal well‐being.