Discovery of Marine Highly Congested Polycyclic Isodhilarane-Type Meroterpenoids as Potential Leads for Treating Liver Fibrosis by Activating the HSF1/AMPK Metabolic Axis

Isodhilarane-type meroterpenoids are a small group of meroterpenoids with highly congested polycyclic skeletons and a wide range of biological activities. However, its antiliver fibrosis actions are rarely reported. Presently, a total of 28 isodhilarane-type meroterpenoids, including nine new ones, were identified based on NMR-guided isolation. By cell-based high-throughput screening, compound 11 (6/7/6/5/6/5 ring system) was demonstrated as the most promising candidate, showing significant antiliver fibrosis activity (IC50 = 0.7 μM) and favorable metabolic stability. Mechanistic studies revealed that 11 significantly inhibits TGF-β1/Smad signaling-mediated fibrogenesis and cell proliferation in activated hepatic stellate cells via activating the central HSF1/AMPK metabolic axis, being more potent than the positive control pirfenidone. Correspondingly, 11 significantly ameliorates liver injury and liver fibrosis in CCl4-treated fibrotic mice. Our findings revealed that isodhilarane-type meroterpenoids represent a novel privileged scaffold with antifibrotic properties, also highlighting compound 11 as a promising candidate for the treatment of liver fibrosis.

异索地罗拉烷型杂萜（isodhilarane-type meroterpenoids）是一类结构高度拥挤的多环骨架杂萜，成员数量稀少且具备广泛的生物活性。然而，其抗肝纤维化作用鲜有报道。本研究依托核磁共振引导的分离（NMR-guided isolation）策略，共鉴定得到28个异索地罗拉烷型杂萜，其中包含9个新化合物。通过基于细胞的高通量筛选（cell-based high-throughput screening），化合物11（具有6/7/6/5/6/5环系）被证实为最具潜力的候选化合物，其抗肝纤维化活性显著（半数抑制浓度IC50=0.7 μM）且代谢稳定性优良。机制研究显示，化合物11可通过激活核心的热休克因子1（HSF1）/腺苷酸活化蛋白激酶（AMPK）代谢轴，显著抑制活化肝星状细胞（hepatic stellate cells）中转化生长因子β1（TGF-β1）/Smad信号通路介导的纤维化进程与细胞增殖，其活性优于阳性对照吡非尼酮（pirfenidone）。相应地，在四氯化碳（CCl4）诱导的肝纤维化小鼠模型中，化合物11可显著改善肝损伤与肝纤维化状况。本研究结果揭示，异索地罗拉烷型杂萜是一类具备抗纤维化特性的新型优势骨架（privileged scaffold），同时凸显化合物11作为治疗肝纤维化的潜在候选药物的开发前景。