Systematic review of Farnesoid X Receptor (FXR) as a therapeutic target in diabetic cardiomyopathy and cardiometabolic diseases

Background Diabetic cardiomyopathy (DCM) is a complex cardiac disorder of diabetes that includes metabolic disorders, oxidative stress, inflammation, myocardial lipid deposition and fibrosis. The Farnesoid X receptor (FXR) is a significant regulator of bile acid, glucose and lipid metabolism and a reported target in cardiometabolic disease. Objective To systematically review the preclinical and clinical data pertaining to both cardiac and cardiometabolic outcomes as well as mechanistic and hepatic outcomes of the effects of FXR modulation, especially FXR activation, in diabetic cardiomyopathy and other cardiometabolic conditions. Methods A systematic literature search was carried out in PubMed/MEDLINE, [Embase if actually searched], Scopus, Web of Science and Google Scholar for eligible studies published from January 2010 until 1 May 2025. Studies in humans and animals that originally reported cardiac, metabolic, hepatic and/or mechanistic outcomes related to FXR modulation were selected. Study selection and reporting was done according to PRISMA 2020. Results The results were heterogeneous between disease models, FXR ligands, study populations, treatment durations, and outcome domains. The most direct evidence of DCM was obtained from experimental diabetic models. OCA treatment reversed cardiac dysfunction, fibrosis, inflammation and oxidative stress, while FXR deletion exacerbated cardiac dysfunction, fibrosis and myocardial lipid accumulation. In human studies, mainly metabolic, hepatic or cholestatic events were measured instead of DCM endpoints. Other studies also reported side effects such as pruritus and lipid parameter changes, which were unfavourable. Conclusion FXR modulation is biologically relevant for pathways related to diabetic cardiomyopathy and cardiometabolic disease. Nevertheless, the current evidence is largely preclinical for DCM and human evidence is largely related to metabolic, hepatic or biochemical outcomes. The different FXR ligands, tissue distribution, and disease contexts should be taken into account when considering the translational potential of FXR-targeted interventions.