Major PM2.5 components promote intracranial aneurysm via TP53: Insights from a comprehensive network analysis

In this study, we combined network toxicology with two-sample Mendelian randomization (MR) to investigate the potential mechanisms by which major components of PM2.5 influence the development of intracranial aneurysms (IAs). We first identified the target genes of six representative PM2.5 constituents (lead, cadmium, arsenic, benzo[a]pyrene, formaldehyde, and benzene) using the Comparative Toxicogenomics Database (CTD). We intersected these with a compiled list of intracranial aneurysm-related genes. This analysis highlighted TP53 as a key hub gene. MR analysis revealed a significant causal association between genetically predicted TP53 expression and aneurysm risk, suggesting that higher TP53 levels may be protective against intracranial aneurysm (odds ratio 0.850; 95 % CI: 0.734-0.985; P = 0.030). Subsequent molecular docking and dynamics simulations showed that PM2.5 components-especially benzo[a]pyrene-bind directly to the TP53 protein, potentially interfering with its function. Single-cell RNA sequencing and gene set enrichment analysis further indicated that high TP53 expression may protect vascular integrity and retard aneurysm progression by regulating pathways related to the cell cycle, apoptosis, inflammation, and oxidative stress. Moreover, protein expression and apoptosis assays in our cell-based experiments corroborated our findings. Together, these results form a chain of evidence linking PM2.5 exposure to intracranial aneurysm phenotypes via TP53. Our findings identify TP53 as the core mediator through which PM2.5 constituents promote intracranial aneurysm formation. This study provides new insight into how air pollution induces cerebrovascular disease and suggests potential molecular targets for intracranial aneurysm prevention and intervention.