The farnesoid X receptor (FXR), a bile acid (BA)-activated nuclear receptor highly expressed in the liver and intestine, regulates the expression of genes involved in cholesterol and bile acid homeostasis, hepatic gluconeogenesis, lipogenesis, inflammation and fibrosis, in addition to controlling intestinal barrier integrity, preventing bacterial translocation and maintaining gut microbiota eubiosis. Non-alcoholic steatohepatitis (NASH), an advanced stage of non-alcoholic fatty liver disease, is characterized by hepatic steatosis, hepatocyte damage (ballooning) and inflammation, leading to fibrosis, cirrhosis and hepatocellular carcinoma. NASH represents a major unmet medical need, but no pharmacological treatments have yet been approved. The pleiotropic mechanisms involved in NASH development offer a range of therapeutic opportunities and among them FXR activation has emerged as an established pharmacological target. Various FXR agonists with different physicochemical properties, which can be broadly classified as BA derivatives, non-BA-derived steroidal FXR agonists, non-steroidal FXR agonists, and partial FXR agonists, are in advanced clinical development. In this review we will summarize key preclinical and clinical features of the most advanced FXR agonists and critically evaluate their potential in NASH treatment.
Keywords: Farnesoid X receptor agonists; combination therapy; liver fibrosis; non-alcoholic steatohepatitis; randomized controlled trials.
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