Objective To investigate the pharmacodynamic effect and mechanism of casticin on improving colitis-associated colorectal cancer (CAC). Methods A CAC mouse model was established using azoxymethane (AOM)/dextran sulfate sodium (DSS) induction, followed by intervention with casticin. Therapeutic efficacy and safety of casticin were evaluated by comparing body weight changes, disease activity index, colonic tumor burden, tumor-bearing survival rates, organ indices, pathological alterations and serum liver function indicators. Intestinal microbiota structural alterations were analyzed using 16S rRNA sequencing. Differentially expressed proteins and key signaling pathways were screened through proteomic techniques. Western blotting was performed to validate key protein expressions. Kaplan-Meier survival analysis based on TCGA database was conducted to evaluate the prognostic value of target genes, and molecular docking was employed to predict the binding modes between casticin and target proteins. The interaction between gut microbiota and host targets was revealed through correlation analysis. Results Compared with model group, casticin significantly alleviated body weight loss in CAC mice, improved intestinal inflammatory responses, reduced colonic tumor volume and tumor burden (P < 0.05), and improved survival rates of tumor-bearing mice. Safety evaluation showed no significant abnormalities in serum liver indicators and histomorphology of major organs in all treatment groups. 16S rRNA sequencing demonstrated that casticin effectively reversed CAC-induced intestinal dysbiosis, significantly downregulated the relative abundance of pro-carcinogenic phyla Fusobacteriota and Patesbacteria, while enriched the anti-inflammatory genera Lachnospiraceae_NK4A136_group and Prevotellaceae_UCG-001 that produce short-chain fatty acids. Proteomic analysis identified the complement and coagulation cascade pathway as the core responsive pathway, with dose-dependent restoration of microenvironment remodeling-related molecule serine protease inhibitor 1 (Serpine1) and immune recognition receptor integrin alpha M (Itgam) expression. Western blotting validation demonstrated that compared with model group, the protein expression levels of Itgam and Serpine1 in colonic tissues were significantly downregulated in casticin group (P < 0.01, 0.001), consistent with the proteomic trend analysis. Integrated analysis further revealed that the abundance of beneficial bacteria such as Lachnospiraceae_NK4A136_group was significantly negatively correlated with the expression of microenvironment remodeling molecule Serpine1, while the abundance of pro-carcinogenic bacteria such as Fusobacteriota was significantly positively correlated with the expression of immune recognition receptor Itgam. Conclusion Casticin can reshape the intestinal microbiota structure, regulate key molecular responses in the complement and coagulation cascade pathway, thereby synergistically blocking the inflammatory-carcinogenic transformation process of CAC.

casticin  /  colitis-associated colorectal cancer  /  gut microbiota  /  proteomics  /  complement and coagulation cascades  /  Itgam  /  Serpine1