Abstract Primary sclerosing cholangitis (PSC) is a rare liver disease of the bile ducts often associated with inflammatory bowel disease (IBD) with a median onset of illness of 35 years and mean progression to death or liver transplantation of 15 years. Currently PSC accounts for approximately 4% of all liver transplants performed in the US and no medical therapies have been shown to be effective in altering the natural history of the disease. Our long term goal is to develop safe and effective therapies for the treatment of PSC. Based upon genome wide association studies and immunologic characterization of the disease, several mechanisms are likely involved in the pathogenesis of PSC. Two potential targets for PSC include Th17 cells and the G protein- coupled receptor for bile acids, TGR5. Similar to other inflammatory diseases, Th17 cells are hyper-responsive in PSC. Variants in the TGR5 gene, a G protein-couple bile acid receptor, have been associated with PSC risk and appear to correlate with low levels of gene expression. Thus, to potential targets for PSC therapies are inhibition of Th17 and activation of TGR5. Recently, ursolic acid (UA), a natural triterpenoid, was found to inhibit Th17 differentiation and IL-17 secretion through its selective antagonist activity on the retinoic acid receptor-related orphan receptor RORt. In addition, UA has been demonstrated to act as a potent agonist of TGR5. UA is found in many medicinal plants and has been extensively studied in animal models. The goals of this study are to 1) measure the pharmacokinetics of orally administered 99%-pure GMP-grade UA in healthy controls and PSC patients, 2) determine the safety and potential efficacy of UA in the treatment of PSC, and 3) understand the impact of UA on Th17 function, macrophage activation, and serum bile acid pools in vivo. To accomplish these goals, we propose a dose escalation study of UA pharmacokinetics, an open label study of UA in PSC, and correlative studies of UA effects on biologic outcomes.