RORC-centered genetic and toxicological signatures connect bisphenols to inflammatory bowel disease

Bisphenols (BPs) are widely used environmental chemicals with endocrine-disrupting and immunotoxic potential. However, their molecular links with inflammatory bowel disease (IBD) remain unclear. We integrated network toxicity, multi-omics framework, and in vitro experiments to investigate BP-associated molecular mechanisms in IBD. Candidate BP–IBD genes were screened by intersecting BP-related targets with IBD-related genes and were further prioritized using transcriptomic and genetic evidence. Immune infiltration and single-cell analyses were used to explore immune-related expression patterns. An IL-17A-stimulated HT29 model was used to assess the effect of BPs expsoure on epithelial inflammatory responses. Fifty overlapping BP–IBD genes were identified and were mainly enriched in IL-17 and TNF signaling pathways, oxidative stress, and lipid metabolic processes. MR combined with bulk RNA-seq prioritized FTO, CDH1, and RORC, while SMR sensitivity analyses further supported RORC and CDH1. Colocalization provided strong evidence for shared causal variants between RORC expression and IBD risk (PPH4 = 0.934), highlighting RORC as the key candidate. Immune infiltration and single-cell analyses suggested that RORC was related to CD4 + T-cell-associated immune regulation in IBD. Molecular docking predicted favorable interactions between RORC and BPs. in vitro experiments showed that BPA further enhanced IL-17A-induced epithelial inflammatory responses, including increased chemokine production and inflammatory signaling activation. BPs may promote IBD-related inflammatory responses through immune-associated mechanisms. RORC may be a key immune-related candidate linking BP exposure to IBD risk.