Discovery of Jatrophane Diterpenoids as JAG1-Notch Signaling Inhibitors for the Treatment of Liver Fibrosis

  • J Med Chem. 2026 Jul 9;69(13):15825-15839. doi: 10.1021/acs.jmedchem.6c00883.
Xin-Ying Zhu  1 ,  Shu-Qi Wu  1 ,  Lu Gan  1 ,  Xianyuan Yang  1 ,  Yi-Ling Liao  1 ,  Nan An  1 ,  Run-Zhu Fan  1 ,  Jia-Luo Huang  1 ,  Gui-Hua Tang  1 ,  Chuan-Rui Zhang  2  3 ,  Sheng Yin  1
Affiliations
  • 1. School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, Guangdong 510006, China.
  • 2. Shandong Laboratory of Yantai Drug Discovery, Bohai Rim Advanced Research Institute for Drug Discovery, Yantai, Shandong 264117, China.
  • 3. Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
PMID: 42314118 DOI: 10.1021/acs.jmedchem.6c00883
Abstract

Liver fibrosis is an urgent clinical condition that lacks effective therapies. In this study, molecular networking-guided fractionation of the medicinal plant Euphorbia hylonoma yielded a focused jatrophane diterpenoid library (1-32), featuring 26 previously undescribed structures. Subsequent antifibrotic screening of this library in TGF-β1-stimulated hepatic stellate cells (HSCs) identified euphylonoid D (1) as a novel hit, enabling a preliminary structure-activity relationship (SAR) analysis of this class. In a CCl4-induced mouse model, 1 significantly alleviated liver fibrosis while exhibiting a favorable safety profile. Mechanistic studies revealed that 1 acts as the first small-molecule inhibitor of Jagged-1 (JAG1), a classic Notch ligand, thereby suppressing Notch signaling, leading to the attenuation of liver fibrosis. These findings not only validate JAG1 as a therapeutic target for liver fibrosis but also highlight 1 as a promising lead for developing novel antifibrotic agents.

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