Ganoderic Acid A alleviates ulcerative colitis by inhibiting the interleukin17 signaling pathway via targeting retinoic acid-related orphan receptor alpha

ETHNOPHARMACOLOGICAL RELEVANCE: Ulcerative colitis (UC), a chronic inflammatory bowel disease, poses a significant global public health burden, a challenge compounded by the limited availability of effective treatments. Ganoderic acid A (GAA), which is a unique secondary metabolite in Ganoderma lucidum, has demonstrated anti-inflammatory, anti-tumor, antioxidant, and lipid-lowering activities. However, the role and mechanism of GAA in UC are not fully understood. AIM OF THE STUDY: In this study, we aimed to explore the role and involved mechanisms of GAA in UC. MATERIALS AND METHODS: We established a dextran sulfate sodium (DSS)-induced UC mouse model to investigate the therapeutic efficacy of GAA in mitigating inflammation and UC. RESULTS: We found that GAA treatment significantly reduced DSS-induced weight loss, colon weight and length reduction, and decreased inflammatory cytokines, while repairing the intestinal epithelial barrier by increasing the expression of tight junction proteins (zonula occludens-1, occludin) and adherent junction protein (α-catenin), suggesting that GAA attenuated DSS-induced UC. Mechanistically, transcriptome sequencing analysis, along with in vivo and in vitro experiments have shown that GAA inhibited the interleukin (IL)-17 signaling pathway. Moreover, we have identified retinoic acid-related orphan receptor alpha (RORA) as a target of GAA through website prediction, molecular docking, and cell thermal shift assay experiments, and further confirmed that GAA inhibited Th17 cells from secreting IL-17 and reduced the polarization of macrophages towards M1 type by decreasing RORA expression. CONCLUSIONS: Our findings disclose that GAA alleviated DSS-induced UC by inhibiting the IL-17 signaling pathway via targeting RORA to reduce inflammation. Our study suggests that GAA holds potential as a nutritional intervention for the prevention and treatment of UC.