Bisphenol A aggravates colitis-associated intestinal epithelial injury: Mitochondrial dysfunction and CASP1-associated inflammatory signaling.

OBJECTIVE: Inflammatory bowel disease (IBD) is characterized by chronic intestinal inflammation and epithelial barrier dysfunction. Environmental contaminants may aggravate epithelial injury, but the underlying mechanisms remain unclear. We investigated how bisphenol A (BPA) affects epithelial mitochondrial function and whether CASP1-associated signaling contributes to injury under IBD-relevant inflammatory conditions. METHODS: Dextran sulfate sodium (DSS)-induced colitis in mice and NCM460 intestinal epithelial cells were used to assess mucosal injury, barrier integrity, mitochondrial dysfunction, and inflammatory responses. CASP1 inhibition with VX-765, computational target prioritization, molecular simulations, and human single-cell transcriptomics were used to evaluate CASP1 involvement, structural plausibility, and disease context. RESULTS: BPA aggravated DSS-induced mucosal injury, reduced ZO-1 and Claudin-1 expression, and increased CASP1 and PTGS2 expression in colon tissues. In NCM460 cells, BPA decreased mitochondrial membrane potential, Complex I activity, and intracellular ATP while increasing mitochondrial superoxide. BPA also increased cleaved CASP1, GSDMD-N, IL-1β, NLRP3, and NF-κB p65 phosphorylation. VX-765 partially improved proliferation, barrier protein expression, and membrane integrity, but did not normalize all inflammatory and metabolic stress responses. Computational analyses prioritized CASP1 as a candidate BPA-IBD-associated molecule and supported the structural plausibility of a potential BPA-CASP1 interaction. Human single-cell analysis identified CASP1-high epithelial cells enriched for inflammatory and pyroptosis-related programs in IBD. CONCLUSION: BPA aggravates colitis-associated intestinal epithelial injury and induces mitochondrial oxidative and bioenergetic dysfunction. CASP1-associated signaling contributes to, but does not fully account for, this epithelial response. Human single-cell data provide complementary context in IBD.