Benzo(a)pyrene aggregating lung inflammation via inducing IL1R1 expression in asthma: Insights from network toxicology, single-cell transcriptomics, and Mendelian randomization.

OBJECTIVE: Exposure to benzo(a)pyrene (BaP) negatively affects lung inflammation in patients with asthma. However, there is a lack of systematic research on the key mechanisms of BaP toxicity in asthma. METHODS: In this study, BaP target genes were predicted using ChEMBL, SEA, and PharmMapper, and asthma-related genes were retrieved from GeneCards, OMIM, and TTD. A protein-protein interaction network was constructed in Cytoscape software using overlapping genes. The causal relationships between core genes and asthma risk were evaluated using Mendelian randomization. BALB/c mice were treated with ovalbumin (OVA) with or without BaP. Single-cell RNA sequencing (scRNA-seq) was performed on mouse lung tissues, and hematoxylin and eosin (HE) staining was used to assess lung inflammation. Molecular docking and molecular dynamics simulations were performed to assess BaP-target interactions. Virtual knockout was performed using scTenifoldKnk. The CIBERSORT algorithm was applied to analyze immune cell infiltration. RESULTS: A total of 23 potential core targets of BaP-induced asthma were initially screened using network toxicology, followed by functional enrichment analysis. The identified target genes were mainly involved in leukocyte migration, immunity, and phosphodiesterase activity, and were enriched in cytokine-cytokine receptor interaction, NF-kappa B signaling pathway, and TNF signaling pathway. Further analysis of the initially selected target genes using machine learning and Mendelian randomization revealed that only IL1R1 remains relevant to asthma, and as IL1R1 expression increases, the risk of asthma onset and exacerbation also increases. Afterward, single-cell sequencing data were obtained from mouse lung tissues (two OVA and two OVA + BaP), and the results verified that BaP induces IL1R1 expression in lymphocytes and vascular endothelial cells. Additionally, molecular docking and molecular dynamics simulations demonstrated that BaP and IL1R1 have strong binding capacity. Virtual knockout of IL1R1 regulated inflammatory responses and immune cell analysis, suggesting that IL1R1 induced mast cell activation. CONCLUSIONS: This study elucidates the mechanism by which BaP exacerbates asthma by modulating the key target IL1R1, offering novel insights into BaP-induced asthma pathogenesis and identifying IL1R1 as a promising biomarker for risk assessment and therapeutic intervention.