Abstract

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.