Casticin Improves Colitis-Associated Colorectal Cancer by Regulating Gut Microbiota-Mediated Complement and Coagulation Cascades
Casticin, a polymethoxyflavone derived from Vitex trifolia, was evaluated for its therapeutic efficacy and mechanism in colitis-associated colorectal cancer (CAC) using an azoxymethane/dextran sulfate sodium (AOM/DSS) mouse model. Casticin intervention significantly attenuated body weight loss, reduced disease activity index, and decreased colonic tumor volume and tumor burden (P < 0.05), while improving survival rates of tumor-bearing mice. Safety assessments revealed no significant abnormalities in serum liver function indicators or major organ histomorphology. 16S rRNA sequencing demonstrated that casticin reversed CAC-induced gut dysbiosis, notably downregulating the pro-carcinogenic phyla Fusobacteriota and Patescibacteria, and enriching anti-inflammatory short-chain fatty acid-producing genera Lachnospiraceae_NK4A136_group and Prevotellaceae_UCG-001. Proteomic profiling identified the complement and coagulation cascades as the core responsive pathway, with dose-dependent restoration of serine protease inhibitor 1 (Serpine1) and integrin alpha M (Itgam) expression. Western blotting confirmed significant downregulation of Itgam and Serpine1 in colonic tissue (P < 0.01 and P < 0.001, respectively), consistent with proteomic trends. Correlation analysis further revealed that beneficial genera such as Lachnospiraceae_NK4A136_group were negatively correlated with Serpine1 expression, whereas pro-carcinogenic Fusobacteriota was positively correlated with Itgam expression. These findings indicate that casticin ameliorates CAC by remodeling gut microbiota composition and modulating key molecules in the complement and coagulation cascades, thereby synergistically blocking the inflammation-to-cancer transition.