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

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.