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

  • Eur J Pharmacol. 2026 May 28:1025:178910. doi: 10.1016/j.ejphar.2026.178910.
Jiangzhou Song  1 ,  Yi Wang  2 ,  Rongrong Guo  2 ,  Kang Wang  2 ,  Yang Hu  2 ,  Ming Cui  2 ,  Guangji Wang  2 ,  Haiping Hao  3 ,  Hong Wang  4 ,  Xiaowei Xu  5
Affiliations
  • 1. State Key Laboratory of Natural Medicines, Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, 211198, China; State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
  • 2. State Key Laboratory of Natural Medicines, Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, 211198, China.
  • 3. State Key Laboratory of Natural Medicines, Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, 211198, China. Electronic address: [email protected].
  • 4. State Key Laboratory of Natural Medicines, Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, 211198, China. Electronic address: [email protected].
  • 5. Institute of Innovative Drug Discovery and Development, China Pharmaceutical University, Nanjing, 211198, China. Electronic address: [email protected].
PMID: 42067015 DOI: 10.1016/j.ejphar.2026.178910
Abstract

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.

Keywords
BAs; Cholesterol 7α-hydroxylase; Farnesoid X receptor; Fibroblast growth factor 15; PBC.
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