Multi-Omics Integration Reveals PBDE-47 as an Environmental Risk Factor for Intracranial Aneurysm via F2R-Mediated Metabolic and Epigenetic Pathways

<b>Background:</b> Intracranial aneurysm (IA) rupture is a life-threatening cerebrovascular event with a mortality rate of up to 40%, affecting approximately 500,000 people globally each year. Although environmental pollutants such as 2,2',4,4'-tetrabromodiphenyl ether (PBDE-47) have been implicated in the pathogenesis of IA, the causal relationship and underlying mechanisms remain unclear. This study aims to systematically explore the potential causal role of PBDE-47 in the development of IA by integrating multi-omics approaches. <b>Methods:</b> We utilized the UK Biobank Drug Proteomics Project (UKB-PPP) genome-wide association study (GWAS) data, including 2940 plasma proteins and 1400 metabolites, along with IA genetic data from 456,348 individuals, to perform a two-sample Mendelian randomization (MR) analysis. Instrumental variables were selected based on genome-wide significance (<i>p</i> < 5 × 10^-8) or suggestive thresholds (<i>p</i> < 5 × 10^-5). Analytical methods included inverse variance weighting (IVW), MR-Egger, weighted median, MR-PRESSO, and Steiger filtering for sensitivity analysis. Molecular docking and 100-nanosecond molecular dynamics simulations were used to evaluate interactions between PBDE-47 and proteins. Mediation analysis assessed the roles of plasma metabolites and miRNAs, and SMR-HEIDI tests were used to verify causal relationships. <b>Results:</b> MR analysis identified 93 plasma proteins potentially causally associated with IA, including 53 protective factors and 40 risk factors. By integrating PBDE-47 targets, IA-related genes, and metabolite-related genes, we identified 15 hub genes. Molecular docking revealed potential binding between PBDE-47 and F2R (binding energy: -5.516 kcal/mol), and SMR-HEIDI testing supported F2R as a potential causal risk factor for IA. Molecular dynamics simulations indicated the stability of the complex structure. Mediation analysis suggested that F2R may influence IA risk through eight plasma metabolites, and miR-130b-3p may indirectly promote IA development by upregulating F2R. <b>Conclusions:</b> Our findings suggest that exposure to PBDE-47 may have a potential causal relationship with IA risk, potentially mediated through the "PBDE-47-F2R-metabolite-miRNA" regulatory axis. These results provide preliminary evidence for early diagnostic biomarkers and targeted interventions for IA. The multi-omics analytical framework established in this study offers new insights into environmental determinants of neurovascular diseases, although further validation is needed to address potential limitations.