Piceatannol Attenuates Benzo[<i>a</i>]pyrene/DSS-Induced Colorectal Cancer in Mice via Modulation of Gut Microbiota and Inhibition of the PI3K/AKT/mTOR Pathway

Benzo[<i>a</i>]pyrene (B[a]P) promotes colorectal cancer (CRC) under chronic inflammation. Piceatannol (PIC), a polyphenol with anti-inflammatory properties, was investigated for its timing-dependent effects in a B[a]P/dextran sulfate sodium (DSS)-induced CRC mouse model. ICR mice received B[a]P and DSS, followed by PIC intervention at different time points. Continuous PIC treatment (PI group) significantly reduced tumor burden, disease activity index, and intestinal permeability. Proinflammatory cytokines significantly decreased, whereas interleukin-10 increased. RNA-seq analysis showed that PIC upregulated transglutaminase 3 (Tgm3), which was associated with suppression of the phosphoinositide 3-kinase/AKT/mechanistic target of rapamycin pathway, downregulation of proinflammatory and tumor-promoting genes, and enhancement of epithelial repair genes. Gut microbiota analysis demonstrated restored microbial diversity, characterized by increased <i>Roseburia faecis</i> and <i>Kineothrix alysoides</i> and a reduction in <i>Turicibacter sanguinis</i> and <i>Romboutsia ilealis</i>. Continuous piceatannol administration attenuates CRC through microbiota and inflammatory regulation, with Tgm3 upregulation potentially contributing to these effects.