Novel treatments targeting metabolic and signaling mechanisms in primary biliary cholangitis

Primary biliary cholangitis (PBC) is characterized by immune-mediated damage of biliary epithelial cells resulting in destruction of small intrahepatic bile ducts with progressive cholestasis, associated with risk for progression to biliary fibrosis, cirrhosis, and hepatocellular cancer. As a result of considerable limitations in our current understanding of the etiology and pathogenesis of PBC, the therapeutic options are still limited. Ursodeoxycholic acid (UDCA) attenuates disease progression and improves survival, but more than 30% of patients do not appropriately respond to UDCA treatment and continue to be at risk for liver-related death or liver transplantation. Thus, new therapeutic approaches are urgently needed. Importantly, bile acids (BAs) have hormonal signaling function via dedicated receptors such as the nuclear receptor farnesoid X receptor (FXR) and G proteincoupled receptor TGR5 (Fig. 1), which regulate BA homeostasis and BA-induced injury and/or inflammation. These receptors are important pharmacological targets in cholestatic disorders such as PBC. In addition,