2. Academic Validation
  3. Discovery of 7-ether substituted homoisoflavonoids as selective FXR modulators attenuating MASH via the FXR and AMPK pathways

Discovery of 7-ether substituted homoisoflavonoids as selective FXR modulators attenuating MASH via the FXR and AMPK pathways

  • Eur J Med Chem. 2026 Jul 5:311:118837. doi: 10.1016/j.ejmech.2026.118837.
Guoning Zhang 1,  Wenqiang Jia 2,  Xinyue Zhou 2,  Shuaishuai Niu 3,  Na Wang 4,  Shaorong Wang 2,  Min Wang 5,  Yihang Hu 6,  Na Zhang 7,  Yi Huan 2,  Hua Sun 5,  Jinsong Liu 4,  Hongwei He 7,  Wei-Shuo Fang 8
Affiliations

Affiliations

  • 1 State Key Laboratory of Bioactive Substances and Functions of Natural Medicine & NHC Laboratory of Biosynthesis of Natural Products, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China; State Key Laboratory of Bioactive Substances and Functions of Natural Medicine, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China.
  • 2 State Key Laboratory of Bioactive Substances and Functions of Natural Medicine & NHC Laboratory of Biosynthesis of Natural Products, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China.
  • 3 State Key Laboratory of Bioactive Substances and Functions of Natural Medicine & NHC Laboratory of Biosynthesis of Natural Products, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China; Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University, Yantai, 264005, China.
  • 4 Guangdong Provincial Key Laboratory of Biocomputing, Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, 510530, China.
  • 5 College of Biotechnology, Tianjin University of Science and Technology, Tianjin, 300457, China.
  • 6 State Key Laboratory of Bioactive Substances and Functions of Natural Medicine & NHC Laboratory of Biosynthesis of Natural Products, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China; Shenyang Pharmaceutical University, 103 Wenhua Rd, Shenyang, 110016, China.
  • 7 NHC Key Laboratory of Biotechnology of Antibiotics, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China.
  • 8 State Key Laboratory of Bioactive Substances and Functions of Natural Medicine & NHC Laboratory of Biosynthesis of Natural Products, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China. Electronic address: [email protected].
PMID: 41950649 DOI: 10.1016/j.ejmech.2026.118837
Abstract

Farnesoid X receptor (FXR) modulation represents a promising therapeutic strategy for metabolic dysfunction-associated steatohepatitis (MASH, formerly NASH); however, the development of MASH drugs from FXR full and partial agonists remains unsucessful. In this study, we employed ring cyclization of our previously identified chalcone FXR antagonists to homoisoflavonoid skeleton and to which attached various 7-ester and ether substituents. Among them, 4l was identified as most potent compound exhibiting high binding affinity and potent cellular antagonistic activity with an IC50 value of 0.70 μM. Molecular docking analysis revealed that the high affinity of 4l is driven by a T-shaped π-π stacking interaction and a robust hydrogen bond network within the FXR binding pocket. Further characterization revealed it functions as a highly selective FXR modulator by regulating the expression of downstream genes responsible for bile acid and lipid transporters (SHP, BSEP, SREBP-1c, and CYP7A1)-while sparing key gluconeogenic genes (PEPCK and G6Pase). In a CDA-HFD-induced MASH mouse model, oral administration of 4l significantly ameliorated hepatic steatosis, ballooning degeneration, and fibrosis, and dyslipidemia. Mechanistic studies further demonstrated that 4l exerts its lipid-lowering effects by activating the AMPK-ACC signaling pathway. Collectively, these findings highlight the 7-ether substituted homoisoflavonoid 4l as a novel, selective FXR modulator with significant therapeutic potential for the treatment of MASH.

Keywords

AMPK-ACC pathway; Farnesoid X receptor (FXR); Homoisoflavonoid; Metabolic dysfunction-associated steatohepatitis (MASH); Selective nuclear receptor modulator (SNRM).

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