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<p>Benzo(a)pyrene (BaP) is a common environmental pollutant from combustion sources that promotes oxidative stress, neuroinflammation and disruption of blood–brain barrier (BBB). However, its contribution to worsening traumatic brain injury (TBI) remains unclear. In this study, we aimed to assess the contribution of BaP to secondary injury in TBI. By integrating data from e.g., the Comparative Toxicogenomics Database, GeneCards, and Online Mendelian Inheritance in Man, 121 overlapping core targets were identified between BaP and TBI. Enrichment analyses via Gene Ontology and Kyoto Encyclopedia of Genes and Genomes, combined with protein–protein interaction networks and topological algorithms (degree, closeness centrality, betweenness centrality, average shortest path length, topological coefficient and partner of multi-edged node pairs), highlighted five hub genes (TP53, EGFR, AKT1, ACTB, and TNF) implicated in mitogen-activated protein kinase signaling, oxidative stress, and neuroinflammation. Molecular docking showed strong binding affinities of BaP to these hub proteins, with energies from -9.3 to -12.1&#xa0;kcal/mol, tighter than co-crystal ligands and existing protein-binding drugs. Molecular dynamics simulations confirmed interaction stability through low root-mean-square deviation (&lt; 0.5&#xa0;nm), fluctuation, and radius of gyration values. Calculation of binding free energies using MM-PBSA validated the strong binding affinity between BaP and binding pockets of each hub genes. Toxicity prediction analysis revealed an oral LD<sub>50</sub> of 316&#xa0;mg/kg for BaP, with high probabilities for neurotoxicity, BBB permeability, carcinogenicity, and mutagenicity, associated with aryl hydrocarbon receptor activation. These findings reveal a "neurovascular homeostasis disruption" network underlying BaP-exacerbated TBI pathology and highlight potential targets to reduce pollution-related risks in TBI management.</p> Graphical Abstract <p>Graphical Headlights</p> <p>1. Systematic exploration reveals a "neurovascular homeostasis disruption" network&#xa0;underlying BaP exposure to exacerbated TBI.</p> <p>2. TP53, EGFR, AKT1, ACTB, and TNF were identified as hub genes in BaP-exacerbated TBI injury.</p> <p>3. Molecular docking, dynamics simulation and MM-PBSA reveal key binding modes and stability.</p> <p></p>

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Exploring potential targets and molecular mechanisms of traumatic brain injury exacerbated by Benzo(a)pyrene via network toxicology and molecular dynamics simulation

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年12月2日

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  • Hantian Hu,
  • Yuetao Hu,
  • Siqi Wan,
  • Qi Wang,
  • Hanyu Li

摘要

Benzo(a)pyrene (BaP) is a common environmental pollutant from combustion sources that promotes oxidative stress, neuroinflammation and disruption of blood–brain barrier (BBB). However, its contribution to worsening traumatic brain injury (TBI) remains unclear. In this study, we aimed to assess the contribution of BaP to secondary injury in TBI. By integrating data from e.g., the Comparative Toxicogenomics Database, GeneCards, and Online Mendelian Inheritance in Man, 121 overlapping core targets were identified between BaP and TBI. Enrichment analyses via Gene Ontology and Kyoto Encyclopedia of Genes and Genomes, combined with protein–protein interaction networks and topological algorithms (degree, closeness centrality, betweenness centrality, average shortest path length, topological coefficient and partner of multi-edged node pairs), highlighted five hub genes (TP53, EGFR, AKT1, ACTB, and TNF) implicated in mitogen-activated protein kinase signaling, oxidative stress, and neuroinflammation. Molecular docking showed strong binding affinities of BaP to these hub proteins, with energies from -9.3 to -12.1 kcal/mol, tighter than co-crystal ligands and existing protein-binding drugs. Molecular dynamics simulations confirmed interaction stability through low root-mean-square deviation (< 0.5 nm), fluctuation, and radius of gyration values. Calculation of binding free energies using MM-PBSA validated the strong binding affinity between BaP and binding pockets of each hub genes. Toxicity prediction analysis revealed an oral LD50 of 316 mg/kg for BaP, with high probabilities for neurotoxicity, BBB permeability, carcinogenicity, and mutagenicity, associated with aryl hydrocarbon receptor activation. These findings reveal a "neurovascular homeostasis disruption" network underlying BaP-exacerbated TBI pathology and highlight potential targets to reduce pollution-related risks in TBI management.

Graphical Abstract

Graphical Headlights

1. Systematic exploration reveals a "neurovascular homeostasis disruption" network underlying BaP exposure to exacerbated TBI.

2. TP53, EGFR, AKT1, ACTB, and TNF were identified as hub genes in BaP-exacerbated TBI injury.

3. Molecular docking, dynamics simulation and MM-PBSA reveal key binding modes and stability.