Anti-Inflammatory Effects of Marine-Derived Resorcylic Acid Lactone Derivatives in Ulcerative Colitis via the MAPK/ERK Pathway

Ulcerative colitis (UC) is an inflammatory bowel disease characterized by recurrent inflammation of the colonic mucosa, and there is currently a lack of safe and effective treatment drugs. Resorcylic acid lactones (RALs) are a natural product that have been reported to have anti-inflammatory effects. However, the mechanism of whether RALs can treat UC and their anti-inflammatory effects remains underexplored. In this study, three new RAL derivatives, Penicillactones A-C (<b>1</b>-<b>3</b>), along with seven known analogs (<b>4</b>-<b>10</b>), were isolated from the marine fungus <i>Penicillium</i> sp. HN20. The structures of compounds <b>1</b>-<b>3</b> were elucidated by spectroscopic methods, ¹³C NMR theoretical calculations, and ECD analysis. Among these, compound <b>4</b> exhibited potent anti-inflammatory activity in LPS-stimulated RAW 264.7 macrophages. In a dextran sulfate sodium (DSS)-induced UC model, compound <b>4</b> alleviated body weight loss, disease activity, colon shortening, and spleen enlargement, and protected intestinal epithelial integrity. Mechanistic studies revealed that compound <b>4</b> primarily exerts its effects by downregulating the Mitogen-Activated Protein Kinase/Extracellular Signal-Regulated Kinase (MAPK/ERK) signaling pathway, inhibiting pro-inflammatory cytokine production. Collectively, these findings provide the first evidence that marine-derived RAL derivatives exert anti-inflammatory effects by inhibiting the MAPK/ERK pathway, highlighting compound <b>4</b> as a promising therapeutic candidate for inflammation and UC.