Bisphenol A promotes esophageal carcinogenesis by activating the MMP1-PCOLCE regulatory axis and remodeling the tumor immune microenvironment.

Bisphenol A (BPA), a ubiquitous environmental endocrine-disrupting chemical extensively used in plastic products, has been increasingly recognized for its carcinogenic potential. However, the molecular mechanisms underlying BPA-associated esophageal carcinogenesis remain incompletely understood. In this study, we integrated transcriptomic differential expression profiling, weighted gene co-expression network analysis (WGCNA), and a comprehensive machine-learning framework incorporating 127 predictive models to systematically identify critical molecular targets involved in BPA-driven esophageal cancer initiation. Single-cell RNA sequencing datasets were further employed to characterize the cell-type-specific distribution of these candidate targets within the tumor microenvironment. Molecular docking and molecular dynamics simulations were conducted to evaluate the binding affinity and interaction stability between BPA and target proteins. SHAP-based interpretability analysis was applied to pinpoint the core regulatory target. Subsequently, scTenifoldKnk virtual gene knockout analysis was utilized to explore downstream signaling mediators. A total of twelve key targets were identified, predominantly enriched in immune and epithelial cell subpopulations at the single-cell level. Docking analyses demonstrated strong binding affinities between BPA and multiple target proteins. Notably, SHAP analysis highlighted MMP1 as the central target mediating BPA-induced esophageal tumorigenesis, which was further supported by molecular dynamics simulations indicating a highly stable interaction. scTenifoldKnk analysis revealed PCOLCE as a potential downstream effector of MMP1 signaling. Collectively, our findings elucidate a previously unrecognized mechanism by which BPA promotes esophageal carcinogenesis through activation of the MMP1-PCOLCE regulatory axis and remodeling of the tumor immune microenvironment. This study provides novel molecular insights and potential therapeutic targets for future toxicological and translational investigations.