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

Authors

Xin-Ying Zhu, Shu-Qi Wu, Lu Gan, Xianyuan Yang, Yi-Ling Liao, Nan An, Run-Zhu Fan, Jia-Luo Huang, Gui-Hua Tang, Chuan-Rui Zhang, Sheng Yin

Published in

Journal of medicinal chemistry. Jun 18, 2026. Epub Jun 18, 2026.

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.

PMID:
42314118
Bibliographic data and abstract were imported from PubMed on 19 Jun 2026.

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