Indigestible carbohydrates suppress colorectal cancer through IRF6/TRAF3/IFNα pathway.

[BACKGROUND] Colorectal cancer (CRC) is one of most common cancers with high morbidity and mortality. Previous studies have indicated that people with higher dietary fiber intake, including non-digestible starch (NDCs), have a lower risk of CRC. The exact mechanism of NDCs in reducing CRC risk and processes remains unclear.

[MATERIALS AND METHODS] IRF6, TRAF3 and IFNα expressions were detected in CRC samples, with subsequent analysis of the correlations between IRF6 and TRAF3 and between IRF6 and IFNα. The effects of sodium butyrate (NaB) on IRF6, TRAF3 and IFNα expression in CRC, cell proliferation, migration and EMT were confirmed in vitro. The interaction between IRF6 and TRAF3 were verified by WB and immunoprecipitation experiments. The effects of NDCs on tumor growth and IRF6 expression were confirmed in vivo.

[RESULTS] Our results showed that IRF6, TRAF3, IFNα expression in CRC was significantly lower than that in adjacent tissues, and IRF6 expression correlated with TRAF3 and IFNα positively. NaB and IRF6 could significantly inhibit the cell proliferation, migration and EMT of CRC cells and IRF6 could bind to TRAF3. NDCs could reduce the lesions of in situ CRC induced by inflammation, and IRF6 expression in colon tissue of mice in NDCs group was significantly increased.

[CONCLUSION] Our study suggested that NDCs intake may regulate IFNα activation by up-regulating IRF6 to inhibit TRAF3 degradation to inhibit the proliferation and migration of tumor cells. Our study will provide theoretical basis and data support for reducing the risk of CRC through dietary regulation and exploring potential therapeutic targets.

[SUPPLEMENTARY INFORMATION] The online version contains supplementary material available at 10.1007/s12672-025-04323-z.