Discovery of vitexin as a novel VDR agonist that attenuates the transition from chronic intestinal inflammation to colorectal cancer

Colitis-associated colorectal cancer (CAC) frequently develops in patients with inflammatory bowel disease (IBD) who have been exposed to a prolonged state of chronic inflammation.

The study of pharmacological agents and their mechanisms for preventing precancerous lesions and inhibiting their progression remains a major objective and challenge in CAC research.

Previous studies have demonstrated that vitexin effectively attenuates ACC, however, its precise mechanism of action warrants further exploration. This study reveals that the absence of the vitamin D receptor (VDR) accelerates the progression of chronic colitis to colorectal cancer. These results indicate that vitexin can specifically target the VDR protein, facilitating its translocation into the cell nucleus to exert transcriptional activity. In addition, using a co-culture model of macrophages and cancer cells, the authors observed that vitexin promotes the polarisation of macrophages towards the M1 phenotype, a process that depends on VDR.

In addition, ChIP-seq analysis revealed that vitexin regulates transcriptional activation of the phenazine biosynthesis domain protein (PBLD) via VDR. ChIP and dual luciferase reporter assays were used to identify the functional regulatory region of PBLD, confirming that the VDR/PBLD pathway is essential for the regulation of vitexin-mediated macrophage polarisation.

Finally, in a mouse model with knockout of the myeloid VDR gene, the authors found that the protective effects of vitexin were abolished at an intermediate stage of ACC.

This study establishes that vitexin targets VDR and modulates macrophage polarisation via the VDR/PBLD pathway, thereby attenuating the transition from chronic colitis to colorectal cancer.