Discovery of Structurally Unusual and Diverse Indole Diterpenoids with Antisteatotic Activity from the Endophytic Fungus Penicillium Paxilli BM-6

Abstract Small molecule accurate recognition technology (SMART)-guided isolation of the endophytic fungus Penicillium paxilli BM-6 afforded 36 indole diterpenoids (IDTs) including eight new ones (1–8). Their structures were elucidated by HRMS and NMR data, DP4+ probability analysis based on calculated NMR chemical shifts, ECD calculations, and X-ray crystallography. Penipaxiline A (1) features an unprecedented 6/5/5/6/7/4 hexacyclic skeleton derived from the paspaline framework, representing a new carbon skeleton in the IDT family. Paxillindole A (2) possesses an unusual 10,30-γ-lactone moiety, whose formation introduces an extra five-membered ring, resulting in a novel 6/5/5/6/6/6/5 heptacyclic system. Antisteatotic activity screening identified 12 active compounds surpassing resmetirom, with compound 23 showing the highest inhibition rate (90.4% at 50 μM). Mechanistically, 23 reduced lipid accumulation by inhibiting lipogenesis and promoting fatty acid oxidation. These findings uncover a new pharmacological application of IDTs for the treatment of metabolic dysfunction-associated steatotic liver disease (MASLD).