Zearalenone exposure is associated with increased tumor burden and coordinated host-microbiota-metabolic alterations in colitis-associated colorectal cancer.

Zearalenone (ZEN) is a common foodborne mycotoxin with intestinal toxicity, but its role in colitis-associated colorectal cancer (CAC) remains unclear. This study evaluated the association between ZEN exposure and CAC progression and explored the related molecular, microbial, and metabolic alterations. Network toxicology was used to predict potential ZEN-related targets and pathways associated with colorectal cancer, suggesting possible involvement of PI3K-Akt, MAPK, and apoptosis-related pathways. Subsequently, an azoxymethane/dextran sulfate sodium (AOM/DSS)-induced CAC model was established in male BALB/c mice, followed by oral gavage of ZEN (0.5 or 1.0 mg/kg) for 4 weeks to evaluate the effects of ZEN exposure on CAC progression in vivo. ZEN exposure was associated with increased tumor burden, more severe histopathological abnormalities, and altered Ki-67 and Caspase-3 staining in AOM/DSS-treated mice. Transcriptomic analysis identified differentially expressed genes related to inflammatory responses, extracellular matrix remodeling, aberrant epithelial regeneration, and lipid metabolism. 16S rRNA sequencing revealed ZEN-associated changes in gut microbial diversity and composition, including enrichment of opportunistic pathogen-associated taxa. Untargeted metabolomics further showed alterations in lipid-related metabolites and metabolic pathways. Correlation-based integrative multi-omics analysis identified a coordinated association network linking host transcriptional changes, gut microbiota alterations, and metabolic remodeling. Overall, repeated high-dose ZEN exposure was associated with increased CAC-related tumor burden and more severe pathological phenotypes under inflammation-prone conditions, together with coordinated host transcriptional, microbial, and metabolic alterations. These findings provide a hypothesis-generating basis for future functional validation of foodborne mycotoxin-host-microbiota interactions in CAC.