Casticin Improves Colitis-Associated Colorectal Cancer by Regulating Gut Microbiota-Mediated Complement and Coagulation Cascades

• • Casticin reduced colonic tumor volume and tumor burden in AOM/DSS mice with P < 0.05, demonstrating statistically significant efficacy in a gold-standard CAC model; this magnitude of tumor load reduction is clinically relevant as it approaches the threshold required for adjuvant therapy candidacy. • • 16S rRNA sequencing showed casticin significantly downregulated Fusobacteriota and Patescibacteria while enriching Lachnospiraceae_NK4A136_group and Prevotellaceae_UCG-001; these shifts correlate with improved barrier function and anti-inflammatory short-chain fatty acid production, offering a microbiome-targeted mechanism distinct from conventional cytotoxic chemotherapy. • • Proteomic and Western blot analyses identified complement and coagulation cascades as the core pathway, with Itgam and Serpine1 downregulated at P < 0.01 and P < 0.001, respectively; these molecules are actionable targets for companion diagnostics and patient stratification in CAC. • • Safety evaluation revealed no significant abnormalities in serum liver function indicators or major organ histomorphology across all treatment groups, indicating a favorable therapeutic index that supports further preclinical development and potential combination with immune checkpoint inhibitors.