Notoginsenoside R1 alleviates cholestatic liver fibrosis through modulation of the intestinal FXR-FGF15 axis and bile acid homeostasis.

Cholestatic liver fibrosis is a progressive liver disease characterized by disrupted bile acid homeostasis, persistent inflammation, and excessive extracellular matrix deposition, for which effective pharmacological therapies remain limited. Although Notoginsenoside R1 (NG-R1), a major bioactive saponin from Panax notoginseng, exhibits anti-fibrotic activity in experimental liver injury, its disease-specific mechanism in cholestatic liver fibrosis remains unclear. Here, C57BL/6 mice subjected to bile duct ligation (BDL) were treated with NG-R1 for 14 days. NG-R1 significantly improved liver function, alleviated hepatic and intestinal injury, suppressed inflammatory responses, and attenuated liver fibrosis. Mechanistically, NG-R1 restored intestinal FXR-FGF15 endocrine signaling by enhancing ileal FXR expression and increasing circulating FGF15 levels, thereby contributing to improved gut-liver bile acid homeostasis. Consistent with these changes, hepatic CYP7A1 expression was reduced, bile acid transporters were coordinately regulated (upregulation of BSEP and OSTα/β and downregulation of NTCP), and hepatic bile acid accumulation was decreased. In Caco-2 cells, NG-R1 increased the expression of FXR, FGF19, Occludin, and ZO-1, whereas these effects were partially abolished by the FXR antagonist guggulsterone, supporting direct activation of intestinal FXR signaling. NG-R1 also partially corrected BDL-induced gut microbial dysbiosis. Collectively, these findings suggest that modulation of the intestinal FXR-FGF15 endocrine axis and restoration of gut-liver bile acid homeostasis contribute to the protective effects of NG-R1 against cholestatic liver fibrosis, providing a mechanistic basis for its therapeutic potential.