Cimicifuga heracleifolia kom. Attenuates ulcerative colitis through the PI3K/AKT/NF-κB signaling pathway

Cimicifuga heracleifolia Kom. (C. heracleifolia) has demonstrated efficacy in treating gastrointestinal disorders, including splenasthenic diarrhea. Ulcerative colitis (UC), a chronic inflammatory bowel disease, shares similarities with splenasthenic diarrhea. However, the pharmacological effects of C. heracleifolia on UC and the underlying mechanisms remain unexplored. The present study investigates the therapeutic potential and mechanisms of C. heracleifolia in UC. Initially, network pharmacology analysis, encompassing ingredient screening, target prediction, protein-protein interaction (PPI) network analysis, and enrichment analysis, was employed to predict the mechanisms of C. heracleifolia. The findings were further validated using transcriptomics and functional assays in a dextran sulfate sodium (DSS)-induced UC model. Additionally, bioactive compounds were identified through surface plasmon resonance (SPR) analysis, molecular docking, and cell-based assays. A total of 52 ingredients of C. heracleifolia were screened, and 32 key targets were identified within a PPI network comprising 285 potential therapeutic targets. Enrichment analysis indicated that the anti-UC effects of C. heracleifolia are mediated through immune response modulation and the inhibition of inflammatory signaling pathways. In vivo experiments showed that C. heracleifolia mitigated histological damage in the colon, reduced the expression of phosphorylated Akt1, nuclear factor-kappa B (NF-κB) p65, and inhibitor of Kappa B kinase α/β (IKKα/β), suppressed the content of interleukin-1β (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α), and enhanced the expression of tight junction proteins. Moreover, cimigenoside, caffeic acid, and methyl caffeate were identified as the bioactive constituents responsible for the UC treatment effects of C. heracleifolia. In summary, this study is the first to demonstrate that C. heracleifolia exerts therapeutic effects on UC by enhancing the intestinal mucosal barrier and inhibiting the phosphatidylinositol 3-kinase (PI3K)/AKT/NF-κB signaling pathway. These findings offer valuable insights into the clinical application of C. heracleifolia for UC management. [Display omitted] •The potential mechanism of Cimicifuga heracleifolia Kom. in ulcerative colitis was firstly reported by network pharmacology-based approach.•Cimicifuga heracleifolia Kom. repaired intestinal barrier.•Cimicifuga heracleifolia Kom. reduced DSS-induced colon inflammati