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.