Project Summary Primary biliary cholangitis (PBC) is a serious, chronic cholestatic liver disease characterized by a progressive, autoimmune-based destruction of the bile duct, and the eventual onset of cirrhosis and its complications. There are limited FDA-approved drugs for the management of PBC, but in many cases liver transplantation is required and offers the only chance for a complete cure. Therefore, effective treatments are urgently needed to treat PBC and to delay time to liver transplantation and to improve the quality of life for PBC patients. With that goal in mind, a novel approach for treating PBC is described below. These developments are based on the observation that remogliflozin etabonate, an SGLT2 inhibitor with unique differentiating properties from other SGLT2 inhibitors, prevents the progression of PBC disease pathology in a murine model of liver damage. Based on our compelling preliminary data, this Phase I confirmation of proof-of-concept study will demonstrate that remogliflozin etabonate is a potential therapy for PBC. We will achieve these goals by the following Aims: 1) Evaluate the role of remogliflozin and other SGLT inhibitors in liver cells in vitro. SGLTs are expressed in biliary ducts and inhibition of SGLTs causes increased biliary flow; and 2) Confirm in vivo our earlier observation that remogliflozin etabonate can prevent or reverse PBC progression using a well-accepted murine model of PBC.