From discovery to mechanism: novel anti-ulcerative colitis meroterpenoids act through the PI3K/IκB-α/MAPK pathway.

UNLABELLED: Ulcerative colitis (UC) is a chronic inflammatory bowel disease for which treatment options remain limited and therapeutic outcomes are often unsatisfactory. In this study, an anti-inflammatory activity-guided investigation led to the isolation of 12 compounds, including 11 new meroterpenoids (1-11) and the known compound aspermeroterpene B (12). Bioaspertermeroterpene A (1) was identified as the first meroterpenoid featuring a novel 6/6/6/7 tetracyclic ring system. In anti-inflammatory assays, compounds 10-12 significantly inhibited lipopolysaccharide (LPS)-induced nitric oxide (NO) production in RAW 264.7 macrophages, with IC50 values of 21.0, 26.7, and 14.1 μmol/L, respectively, outperforming the positive control indomethacin (IC50 = 24.1 μmol/L). These compounds also downregulated the protein expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2). Further mechanistic investigations revealed that compound 12 exerts its anti-inflammatory effects by modulating the PI3K/IκB-α/MAPK signaling pathway. In a dextran sulfate sodium (DSS)-induced murine colitis model, compound 12 demonstrated remarkable therapeutic efficacy by alleviating disease symptoms, restoring intestinal barrier integrity, and suppressing colonic inflammation by downregulating iNOS and tumor necrosis factor-α (TNF-α). Collectively, this study not only reveals a class of structurally novel meroterpenoids with potent anti-UC activity but also identifies compound 12 as a highly promising lead candidate for the treatment of inflammatory bowel disease. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at https://doi.org/10.1007/s42995-026-00371-8.