FCRL3 as a potential link between Benzo[a]pyrene exposure and primary biliary cholangitis: insights from comparative toxicogenomics and multi-omics analysis

BACKGROUND: Exposure to Benzo[a]pyrene (BaP) is linked to multiple autoimmune diseases. This study aims to identify the key genes associated with BaP exposure and primary biliary cholangitis (PBC), shedding light on the underlying molecular mechanisms. METHODS: Comparative toxicogenomics was employed to identify genes shared between BaP targets and PBC. Quantitative trait loci data for methylation, gene expression, and proteins, as well as genome-wide association study data for PBC, were collected. Subsequently, Summary Data-based Mendelian Randomization (SMR) was utilized for analysis. Molecular docking assessed the binding affinity between BaP and the Fc receptor-like 3 (FCRL3) protein. The single-cell technique was further applied to explore the cell types with the highest FCRL3 expression. Finally, we performed in vitro validation using Raji cells. RESULTS: Through comparative toxicogenomic analysis and integration of multi-omics evidence, FCRL3 was identified as a potential key link between BaP exposure and PBC. Cross-validation in independent datasets and multiple tissues provided additional support for the robustness of these findings. Single-cell RNA sequencing further revealed predominant FCRL3 expression in B cells. Ultimately, cellular experiments demonstrated that BaP not only influenced the expression levels of FCRL3, but also directly bound to the protein (binding energy: -5.98 kcal/mol). CONCLUSION: This study integrates multi-level molecular data to highlight the potential role of BaP in PBC pathogenesis through its target gene FCRL3, offering a new mechanistic insight into the relationship between BaP exposure and PBC development.