Integrative network toxicology and single-cell analysis implicates a potential TGFBR1-centered fibroblast remodeling axis in Benzo[a]pyrene-related atrial fibrillation

Background Benzo[a]pyrene (BaP), an air pollution-related polycyclic aromatic hydrocarbon, may intersect with molecular pathways relevant to atrial fibrillation (AF), but this relationship remains unclear. Objectives To examine whether predicted BaP targets overlap with molecular and cellular remodeling features in human AF-related atrial datasets. Methods Five AF microarray datasets and one single-cell RNA sequencing (scRNA-seq) dataset were analyzed. Differential expression and weighted gene co-expression network analysis (WGCNA) defined AF-associated key genes directly observed from human AF transcriptomic datasets. BaP predicted targets were computationally obtained using ChEMBL, Similarity Ensemble Approach (SEA), and PharmMapper; their overlap with AF-associated key genes defined inferred BaP–AF candidate targets for Gene Ontology (GO)/Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment. Machine learning (ML) with SHapley Additive exPlanations (SHAP) prioritized hub genes. Cell-type Identification By Estimating Relative Subsets Of RNA Transcripts (CIBERSORT), docking, and single-cell analyses assessed immune patterns, structural plausibility, and cellular context. Results Eighteen inferred BaP–AF candidate targets were identified by overlapping AF-associated key genes with BaP predicted targets, and these candidates were enriched in oxidative stress/inflammation and transforming growth factor-beta (TGF-β)-related remodeling pathways. Elastic Net yielded a final hub-gene signature (PPP3CA, ERBB4, PSAP, LAMP1, PPARA, HSP90AB1, TGFBR1, KCNA5). AF exhibited increased neutrophils and reduced M2 macrophages/T follicular helper (Tfh) cells. Single-cell analyses of AF-related human atrial tissue localized the hub genes to major cell populations and revealed AF-associated immune expansion and fibroblast-centered TGF-β signaling, dominated by TGFB1–(TGFBR1 + TGFBR2), rather than directly measuring BaP-induced single-cell remodeling.scTenifoldKnk-based TGFBR1 virtual knockout highlighted perturbations (ABCA8, CD9, IFI44L, BGN). Conclusion These findings nominate a testable hypothesis that BaP-related target perturbations may intersect with TGFBR1-associated fibroblast remodeling in AF. Future studies should evaluate this hypothesis in exposure-relevant atrial cell models through controlled BaP exposure and TGFBR1 gain- or loss-of-function experiments, followed by in vivo validation of fibroblast activation and atrial remodeling.