Unraveling the potential carcinogenic risk of bisphenols: a comprehensive network analysis and computational toxicology insights

Bisphenols (BPs), including bisphenol A (BPA) and its analogs BPB, BPF, BPS, and BPAF, are essential industrial raw materials used in the production of consumer goods but pose significant public health risks. Bisphenols contribute to carcinogenesis due to their endocrine-disrupting properties, particularly in breast cancer. However, the relationship between BPs exposure and putative cancer risk, as well as the underlying molecular mechanisms, remains poorly understood. This study employed network toxicology, molecular docking, molecular dynamics simulation, machine learning, and bioinformatics to systematically investigate the molecular mechanisms and potential targets associated with carcinogenic risks of five BPs. The findings revealed that BPs exposure increases cancer risk by targeting 26 core proteins, including RXRA, AKT2, and CYCS, leading to oxidative stress and modulation of cancer-related signaling pathways such as MAPK, PI3K/AKT, Ras, and VEGF. Molecular docking and dynamics simulations demonstrated stable binding interactions between RXRA and all five BPs. Analysis of the TCM database indicated that Ginseng, Turmeric, and Salvia miltiorrhiza can mitigate BPs-induced cancer risk by targeting these core proteins. Pan-cancer analysis showed that kidney renal clear cell carcinoma (KIRC) and low-grade glioma (LGG) are most strongly associated with BPs exposure. Diagnostic and prognostic models based on core targets exhibited high predictive accuracy, offering valuable clinical decision support. Single-cell sequencing revealed that core targets are primarily localized in immune cells in KIRC and glioma cells in LGG. This study provides a theoretical foundation for evaluating cancer risk associated with BPs exposure and establishes a novel framework for understanding the pathogenesis and potential therapeutic strategies for environmental pollutants.