Deciphering the carcinogenic role of benzo[a]pyrene in glioblastoma: Insights from network toxicology, single-cell transcriptomics, and Mendelian randomization
Liye Yi, Wencai Wang, Zhonghua Sun, Y. Chen, Zijie Xiong, Lingling Ma, Wei Ye, Xianfeng Li
Abstract
Benzo[ a ]pyrene (BaP) is a known environmental carcinogen linked to multiple tumors, but its role in glioblastoma (GBM) remains poorly understood. This study aimed to explore BaP’s tumorigenic mechanisms in GBM through an integrated approach combining network toxicology, single-cell transcriptomics, Mendelian randomization, and bibliometric analysis. BaP target genes were predicted using ChEMBL, SEA, and PharmMapper, and GBM-related genes were retrieved from GeneCards, OMIM, and TTD. Overlapping genes were used to construct a protein–protein interaction network in Cytoscape. Molecular docking and molecular dynamics simulations were performed to assess BaP–target interactions. Single-cell RNA-seq data (GSE131928) were analyzed to profile gene expression in GBM subpopulations. Mendelian randomization assessed causal relationships between core genes and GBM risk, and findings were validated in vitro. Bibliometric analysis tracked research trends on these genes. 31 overlapping genes were identified. TP53 was highly expressed in MES-like and AC-like malignant cells as well as CD8⁺ Tex cells. MR revealed a significant inverse association between TP53 expression and GBM risk (OR = 0.13, 95 % CI: 0.04–0.47, p = 0.002). Docking and simulation showed strong BaP–TP53 binding, confirmed by in vitro experiments. Bibliometrics indicated that TP53 research in GBM has shifted from basic mechanisms to clinical translation. BaP may drive GBM by targeting TP53, offering insights for GBM prevention and therapy. • Identified TP53 and HSP90AA1 as key BaP-related targets in GBM through network toxicology and molecular docking. • Single-cell and Mendelian randomization analyses revealed TP53 as highly expressed and causally protective against GBM. • Findings suggest BaP may promote GBM by disrupting TP53, offering new insights into environmental carcinogenesis in the brain.