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 <b>11</b> (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 <b>11</b> 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, <b>11</b> 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 <b>11</b> as a promising candidate for the treatment of liver fibrosis.