Benzo[a]pyrene exacerbates atherosclerosis by upregulating SPP1 to promote macrophage inflammation and lipid dysregulation : An integrated network toxicology, RNA-seq, and experimental validation study

Li, R. and Zheng, J. and Tang, Y. and Liu, A. and Liu, J. and Cai, S. (2026) Benzo[a]pyrene exacerbates atherosclerosis by upregulating SPP1 to promote macrophage inflammation and lipid dysregulation : An integrated network toxicology, RNA-seq, and experimental validation study. Vascular Pharmacology, 162: 107589.

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Abstract

Benzo[a]pyrene (BaP), a pervasive environmental pollutant, has been implicated in cardiovascular injury, yet its mechanistic contribution to atherosclerosis remains unclear. Here, we combined network toxicology, RNA-seq profiling, molecular simulations, and cellular validation to elucidate BaP-driven vascular effects. Integration of BaP-associated targets with atherosclerosis gene sets identified SPP1 as a key hub. Transcriptomic analysis of aortas from BaP-treated ApoE−/− mice revealed differential expression enriched in inflammatory responses, cytokine signaling, xenobiotic metabolism, and lipid-handling pathways. STRING-based protein interaction networks and Reactome analysis further supported coordinated activation of innate immunity and metabolic dysfunction. Molecular docking and 100-ns MD simulations demonstrated stable, energetically favorable binding between BaP and SPP1. In THP-1 macrophages, BaP enhanced oxLDL-induced SPP1 expression, reduced cell viability, and promoted a foam-cell-like phenotype characterized by suppressed ABCA1 and increased CD36 and PLIN2. Silencing SPP1 partially rescued BaP-induced cytotoxicity and lipid dysregulation, confirming SPP1's functional involvement. Collectively, these findings indicate that BaP aggravates atherosclerosis through SPP1-mediated macrophage inflammation and impaired lipid metabolism, highlighting SPP1 as a potential mechanistic link and therapeutic target for pollution-exacerbated vascular disease.