Bile acid signaling in MASLD: from pathogenesis to therapeutic applications

Abstract

The increasing prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) causes considerable global morbidity and mortality. Dysregulated lipid and glucose metabolism are central elements in the pathogenesis of MASLD by promoting hepatocellular stress, inflammation, and liver fibrosis that may culminate in the development of cirrhosis and liver cancer. Moreover, intestinal dysbiosis and bacterial translocation trigger hepatic and systemic inflammation, further contributing to the pathogenesis and progression of MASLD. Bile acid (BA) receptors regulate hepatic metabolism and gut integrity as central players in the pathophysiology of MASLD. Therapeutic strategies targeting these BA receptors along the gut-liver axis, either directly through agonists or indirectly via modulation of BA transport, are currently within the focus of clinical research. This review summarizes mechanistic aspects of BA signaling in MASLD, key evidence of experimental and clinical studies on BA receptor agonists and provides an outlook for future opportunities and challenges on the road to the implementation of novel therapies targeting BA receptors and BA signaling in MASLD.