Unprecedented Meroterpenoids Exert Anti-inflammatory Activity by Targeting NF-κB and PI3K Signaling Pathways

Four classes of unprecedented meroterpenoids (<b>1</b>-<b>10</b>), together with 10 new analogues, were isolated from the symbiotic fungi biotransformation extract. Among them, compounds <b>1</b>-<b>3</b> were characterized as the inaugural meroterpenoids containing a 5/3/6/6/6 fused carbon ring system. Compounds <b>4</b> and <b>5</b> were identified as the first meroterpenoids featuring the rare 6/6/6/6 tetracyclic carbon skeleton. Compound <b>6</b> stood out as the first meroterpenoid exhibiting a novel 5/3/6/6/5 pentacyclic framework. Notably, compounds <b>7</b>-<b>10</b> were reported as a novel 6/6/6/5 carbon skeleton architecture. Furthermore, <b>1</b> and <b>6</b> showed stronger inhibitory activities against lipopolysaccharide (LPS)-induced nitric oxide (NO) production in RAW 264.7 cells with IC₅₀ values of 7.46 and 6.02 μM, respectively, than the positive control (indomethacin, IC₅₀ = 31.17 μM). Meanwhile, <b>1</b> and <b>6</b> significantly downregulated the expression of inflammatory enzyme iNOS and also inhibited the phosphorylation of NF-κB, PI3K, and IκB-α in a concentration-dependent manner.