Dehydrodiisoeugenol targets NOD2 exerting dual effects against colitis and colorectal cancer: a double-edged sword

Abstract

Dehydrodiisoeugenol (DEH) is a primary benzofuran-type neolignan isolated from the Chinese herbal medicine nutmeg, which is used in the treatment of gastrointestinal diseases. This study aims to observe the dual therapeutic effects of DEH on DSS-induced ulcerative colitis (UC) and colorectal cancer (CRC), with a focus on exploring the molecular mechanism by which DEH exerts anti-inflammatory effect in inflammatory cells and induces autophagy in CRC cells. An inflammatory cell model was established by LPS/IFNγ-stimulated RAW264.7 macrophages to observe the anti-inflammatory effect of DEH, while colon cancer cell lines were used to observe the anticancer activity of DEH. DSS-induced mice and subcutaneous tumor model in nude mice were also established to observe the bidirectional regulation of DEH. This study demonstrates that low concentrations of DEH exhibit anti-inflammatory effects in vitro. Importantly, DEH achieves significant inhibition of IκBα degradation and phosphorylation levels, as well as subsequent NF-κB nuclear translocation, while also suppressing the phosphorylation of the MAPK family members JNK, ERK, and p38, by reducing elevated NOD2 expression induced by LPS/IFNγ. In addition, oral administration of DEH improves colitis and colonic barrier damage in DSS-induced mice. Interestingly, at a high concentration of DEH significantly activates the NOD2 signaling pathway to promote autophagy and apoptosis in CRC cells, contributing to its anti-CRC effect. These findings suggest that different concentration of DEH shows bidirectional regulation by improve inflammatory responses in UC and simultaneously possess anti-CRC effects by targeting the NOD2. This highlights DEH as a promising candidate for clinical treatment of UC and CRC.