Gaseous Air Pollutant Exposure and Atherosclerosis: A Systematic Study Integrating Multi-Omics and Network Toxicology

Gaseous air pollution is a major environmental risk factor for atherosclerosis, yet the specific molecular networks linking Gaseous air pollution to atherosclerosis are not fully characterized. This study aimed to elucidate how gaseous pollutants drive atherosclerosis using a multi-level framework integrating network toxicology, nine machine-learning algorithms, bulk and single-cell/spatial transcriptomics, molecular docking, clinical tissue/serum validation, and in vitro pollutant-exposure assays. A conserved RXRA–MMP9–TNF axis was identified as a core molecular network linking pollutant exposure to atherosclerosis. Single-cell and spatial transcriptomics showed broad expression of RXRA (Retinoid X Receptor Alpha) in vascular stromal and endothelial cells and its association with xenobiotic and lipid metabolism, whereas MMP9 (Matrix Metallopeptidase 9) and TNF (Tumor Necrosis Factor) were enriched in macrophages, T cells, and mast cells within plaques, correlating with immune cell infiltration. Multiple pollutants displayed high binding affinity to these proteins. Clinical samples showed upregulation of these targets in atherosclerotic tissue and serum. Toluene exposure in THP-1-derived macrophages significantly increased RXRA, MMP9, and TNF mRNA and protein levels. These findings highlight an immune–metabolic interplay centered on the RXRA–MMP9–TNF axis in Gaseous air pollution-driven atherosclerosis, supporting these molecules as candidate biomarkers for environmental health strategies.