Discovery of Myrsinane Diterpenoids from <i>Euphorbia prolifera</i> as a New Type of Antiliver Fibrosis Agents That Inhibit the PI3K-AKT Signaling Pathway

Liver fibrosis represents an unmet clinical need. Building on the high screening hit rate of Euphorbiaceae diterpenoids in our previous antifibrotic campaigns, we constructed a library of 29 myrsinane diterpenoids from the roots of <i>Euphorbia prolifera</i> in the current study. This collection features three skeletal subtypes and includes 13 new compounds, euphpronoids A-M (<b>1</b>-<b>13</b>), whose structures were elucidated by comprehensive spectroscopic analyses, ECD calculations, chemical correlation, and single-crystal X-ray diffraction. Antiliver fibrosis screening of this library in TGF-β1-stimulated LX-2 cells revealed that 10 compounds significantly suppressed fibronectin (FN) expression. The most active hit, compound <b>11</b>, dose-dependently reduced the protein levels of FN, α-smooth muscle actin, and collagen I. Mechanistic studies indicated that <b>11</b> exerts its antifibrotic effect by inhibiting the PI3K-AKT signaling pathway. These findings underscore the potential of the myrsinane scaffold as a promising structural motif for antiliver fibrosis drug development.