Intestinal-restricted Farnesoid X receptor agonist Fex3 alleviates cholestatic liver injury via FGF15-CYP7A1 axis.

Maintaining bile acids (BAs) homeostasis is a recognized key strategy for treating primary biliary cholangitis (PBC), with the farnesoid X receptor (FXR) playing a significant regulatory role in this process. Compared to systemic FXR agonists, activation of intestinal FXR also benefit to BAs homeostasis, which have limited target genes, intestinal FXR activation may cause milder side effects. In this study, we evaluated the therapeutic efficacy, mechanism of action, and pharmacokinetic properties of Fex3 (fexaramine-3, an intestinal-restricted FXR agonist previously synthesized by our team) for cholestasis therapy. Results showed that Fex3 effectively alleviated cholestatic liver injury by activating the intestinal FXR-fibroblast growth factor 15 (FGF15) signaling pathway, which subsequently suppressed hepatic cholesterol 7α-hydroxylase (CYP7A1) expression. In mouse models, Fex3 demonstrated good tolerability and an excellent safety profile. These findings indicate that the intestinal- restricted FXR agonist Fex3 represents a promising novel therapeutic agent for PBC, providing a new insight into intervention for PBC targeting FXR.