Introduction: This study aims to systematically elucidate the potential molecular targets and core signaling pathways underlying bisphenol A (BPA)-induced diabetic nephropathy (DN) through the integration of network toxicology and molecular docking approaches. Methods: Using multiple public databases—including ADMETlab 2.0, ProTox-III, SwissTarget- Prediction, GeneCards, OMIM, TTD, and the PDB—we systematically identified the potential therapeutic targets of BPA and the disease-associated targets of DN. Overlapping targets between the two sets were rigorously extracted using Venn diagram analysis. Subsequently, a BPA-DN protein- protein interaction network was constructed and visualized using Cytoscape. Functional enrichment analyses (GO and KEGG) were performed to clarify the biological processes and signaling pathways involved. Finally, molecular docking simulations between BPA and top-ranked hub targets were conducted using CB-Dock2 to evaluate binding feasibility and stability. Results: A total of 42 potential therapeutic targets of BPA in DN were identified through integrative bioinformatic analysis. Functional enrichment analysis indicated that immune-inflammatory response and programmed cell death were the predominant biological processes associated with BPA-induced toxicity. Molecular docking simulations demonstrated stable binding conformations between BPA and six core targets—ESR1, PTGS2, MMP2, BCL2, MMP9, and INS—with binding energies ranging from -6.1 to -8.6 kcal/mol, suggesting strong binding affinity. Pathway enrichment analysis further indicated that the MAPK, PI3K-Akt, and NF-κB signaling pathways act as central mediators in BPA-associated DN pathogenesis. Discussion: This study clarifies the molecular mechanism by which BPA may induce DN through multitarget and multipathway approaches. The findings not only provide a new theoretical framework for understanding the pathogenesis of BPA-induced nephrotoxicity but also demonstrate the effectiveness of network toxicology in identifying toxic pathways of environmental pollutants. Moreover, they offer a scientific basis for the prevention of BPA-related diabetic complications and the development of targeted therapeutic strategies. Conclusion: BPA may influence the secretion and sensitivity of INS by interfering with the ESR1- mediated hormone signaling pathway, affecting the expression of PTGS2, MMP2, and MMP9, modulating BCL2, and ultimately promoting the pathological progression of DN.
Li et al. (Thu,) studied this question.