Discovery of myrsinane diterpenoids from Euphorbia prolifera as a new type of anti-liver fibrosis agents that inhibit PI3K-AKT signaling pathway

Liver fibrosis represents an unmet clinical need. Building on the high screening hit rate of Euphorbiaceae diterpenoids in our previous anti-fibrotic campaigns, we constructed a library of 29 myrsinane diterpenoids from the roots of Euphorbia prolifera in the current study. This collection features three skeletal subtypes and includes 13 new compounds, euphpronoids A-M (1-13), whose structures were elucidated by comprehensive spectroscopic analyses, ECD calculations, chemical correlation, and single-crystal X-ray diffraction. Anti-liver fibrosis screening of this library in TGF-ß1-stimulated LX-2 cells revealed ten compounds that significantly suppressed fibronectin (FN) expression. The most active hit, compound 11, dose-dependently reduced the protein levels of FN, a-smooth muscle actin, and collagen I. Mechanistic studies indicated that 11 exerts its anti-fibrotic effect by inhibiting the PI3K-AKT signaling pathway. These findings underscore the potential of the myrsinane scaffold as a promising structural motif for anti-liver fibrosis drug development. Overall design: LX-2 cells mRNA profiles of treatment with TGF-ß1+ DMSO or TGF-ß1 + 10 µM 11 for 48 h.