Hedyotis diffusa Suppresses Colitis-Associated Colorectal Cancer via Inhibition of the IL-17A-IL-17RA Axis and NF-κB Signaling.

Chronic inflammation-driven colorectal cancer (CRC) is critically mediated by interleukin-17A (IL-17A)-dependent immune responses and nuclear factor-κB (NF-κB) signaling, which promote immune cell infiltration and tumor progression. In this study, the anti-tumor efficacy and molecular mechanisms of a standardized extract of Hedyotis diffusa Willd. (HD) and its constituent, ferulic acid (FA), were investigated using an azoxymethane/dextran sulfate sodium (AOM/DSS)-induced colitis-associated CRC mouse model. HD and FA treatment markedly alleviated colitis, reduced tumor number and size, improved survival, and attenuated histopathological damage. Transcriptomic analysis revealed significant modulation of immune-related pathways, with prominent suppression of IL-17A and NF-κB signaling. Molecular docking demonstrated binding of FA to IL-17A at Pro59 and Arg101, suggesting potential disruption of the IL-17A/IL-17RA interaction. Consistently, both HD and FA reduced immune cell infiltration, downregulated IL-17A production, and inhibited NF-κB activation in colonic tissues. Collectively, these findings demonstrated that HD exerted protective effects against inflammation-associated CRC through targeting the IL-17A/IL-17RA axis and downstream NF-κB signaling, providing mechanistic insight into IL-17A-centered immunomodulation in colorectal tumorigenesis.