Pollutant-induced activation of the AHR–NF-κB–C/EBPβ axis in colorectal cancer

This study identified environmental pollutants associated with activation of the AHR–NF-κB–C/EBPβ signaling axis and examined their effects in colorectal cancer (CRC). ToxCast indicators and TCGA-COAD/READ RNA-seq data were integrated to construct a pollutant-response matrix; an SVM model prioritized phenmedipham for mechanistic testing. In vitro, phenmedipham increased AHR, p-p65, and C/EBPβ expression and pro-inflammatory cytokine secretion, whereas pathway-component silencing attenuated these effects. In vivo, phenmedipham increased colonic tumor burden and histopathological damage; pathway inhibition mitigated these phenotypes. Immunological analyses indicated impaired dendritic-cell activation and T-cell effector responses. These results provide preclinical evidence that phenmedipham can modulate inflammatory signaling and tumor-associated phenotypes in the tested models. They do not establish human carcinogenicity, CRC risk, or population-level exposure–disease causality; epidemiological validation is required.