Network Toxicology, Molecular Docking, and Molecular Dynamics Simulations Reveal the Mechanism of Tetrabromobisphenol A in Bullous Pemphigoid

Abstract Bullous pemphigoid (BP) is an autoimmune blistering disease with a growing incidence, and environmental factors are receiving increasing attention. Tetrabromobisphenol A (TBBPA), a widely used brominated flame retardant, is a significant environmental pollutant. However, the molecular mechanisms by which TBBPA contributes to BP pathogenesis remain unclear. This study integrated network toxicology, molecular docking, and molecular dynamics (MD) simulations to systematically investigate the molecular mechanisms of TBBPA-induced BP. Using network toxicology, we identified 797 potential targets of TBBPA and 446 BP-related targets. A Venn diagram analysis revealed 48 common targets. Protein-protein interaction (PPI) network and topological analyses further identified five core hub targets: TNF, CXCL8, MMP9, ICAM1, and ITGB1. Gene enrichment analysis indicated that these targets were significantly enriched in immune-inflammatory pathways, such as leukocyte migration, inflammatory responses, and the IL-17 signaling pathway, as well as in various pathogen infection and cancer-related pathways. Molecular docking revealed that TBBPA stably binds to all five core targets with binding energies ≤ -5 kcal/mol, driven primarily by hydrophobic interactions and π-π stacking. Subsequent MD simulations confirmed that TBBPA complexes with TNF, CXCL8, and MMP9 remained stable throughout the 100 ns simulation. The overall protein structures remained compact, and the ligands were effectively encapsulated within the binding pockets, forming stable networks of hydrogen bonds and hydrophobic interactions. In conclusion, this study, for the first time, proposes a systematic molecular framework using integrated computational biology. Our findings suggest that the environmental pollutant TBBPA may act as a potential risk factor in BP pathogenesis by targeting core proteins (TNF, CXCL8, and MMP9). These interactions potentially disrupt critical signaling pathways related to immune inflammation, cell migration, and tissue remodeling. This study offers a novel mechanistic hypothesis regarding environmental chemical exposure in autoimmune blistering diseases, although further experimental validation is required. Highlights Network toxicology identified 48 common targets linking Tetrabromobisphenol A(TBBPA) exposure to Bullous Pemphigoid (BP). Five core targets (TNF, CXCL8, MMP9, ICAM1, ITGB1) were screened as potential mediators. TBBPA stably binds to TNF, CXCL8, and MMP9 with binding energies ≤ -5 kcal/mol. Molecular dynamics simulations confirm stable binding and structural integrity of complexes. This study provides a mechanistic framework for TBBPA as an environmental risk factor in BP.