Protective potential of nodakenin in high-fat diet-mediated colitis-associated cancer: Inhibition of STAT3 activation and Wnt/β-catenin pathway, and gut microbiota modulation.

A high-fat diet (HFD) exerts complex effects on the risk of colitis-associated cancer (CAC). Nodakenin, a key phytochemical isolated from the dried roots of Angelicae gigas Nakai (Umbelliferae), possesses anti-inflammatory and anti-adipogenic properties and shows potential as a therapeutic agent for colorectal cancer (CRC). In this study, we investigated the protective effects and underlying molecular mechanisms of nodakenin in an animal model of CRC induced by HFD, azoxymethane (AOM), and dextran sodium sulfate (DSS). Oral administration of nodakenin significantly alleviated clinical symptoms, such as recovery of weight, spleen weight, and colon length, and suppressed tumor progression in the colonic tissues of HFD/AOM/DSS-induced CRC mice. Nodakenin inhibited the activation of STAT3-related inflammatory mediators and downregulated proteins involved in the Wnt/β-catenin signaling pathway. These effects contributed to the disruption of epithelial-mesenchymal transition (EMT) and the restoration of tight junction integrity within the colonic tissue. Furthermore, nodakenin treatment improved the composition of the gut microbiota, leading to observable species-level differences. Network analysis revealed significant correlations between clinical parameters, inflammatory markers, EMT and apoptotic factors, and the composition of the gut microbiota. Specifically, negative correlations were observed between spleen weight and Alistipes, as well as between MCP-1 and Clostridium_g21. Positive correlations with spleen weight were observed with species belonging to Anaerotruncus, Emergencia, and Parvibacter. Bacteroidaceae_uc and Bacteroides correlated positively with MCP-1, Streptococcus correlated positively with PUMA, and Harryflintia, Odoribacteraceae_uc, and Roseburia correlated positively with cleaved caspase-3. Overall, our findings suggested that nodakenin effectively alleviates HFD/AOM/DSS-induced CRC by targeting inflammatory pathways (STAT3 and Wnt/β-catenin), suppressing EMT, and restoring gut microbiota balance. These multiple mechanisms underscore its potential as a promising agent for the prevention and treatment of colitis-associated colorectal cancer.