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.