Zhang_2025_Comb.Chem.High.Throughput.Screen__

BACKGROUND: Atherosclerosis (AS) is a leading cause of cardiovascular diseases, characterized by lipid accumulation in arterial walls. The enzyme Ephx2 (soluble epoxide hydrolase, sEH) is implicated in AS development, but its precise mechanisms and therapeutic potential are not fully understood. OBJECTIVES: This study aimed to analyze gene expression data from low-density lipoprotein receptor knockout (LDLR/) and LDLR/sEH/ mice to identify significant genes associated with AS. METHODS: A directed compound-protein interaction network was constructed based on these genes and related pathways from the Kyoto Encyclopedia of Genes and Genomes (KEGG) database. In the end, through resistance distance (RD) between any two nodes in this network, the Independent Cascade (IC) model was applied to explore Ephx2 mechanisms in AS, such as important Adverse Outcome Pathways (AOPs). RESULTS: Several AOPs were identified as critical in AS treatment via Ephx2. The key AOPs included inflammatory response and cytokine release, cholesterol deposition and oxidation, disruption of plaque stability, smooth muscle cell proliferation and migration, and platelet activation and coagulation. Within the top AOPs of inflammatory response and cytokine release, potential target genes were identified, such as Mapk3, PiK3cd, Gnai2, Mapk10, Arnt, and RhoA. Critical paths from Ephx2 to these target genes were established, suggesting mechanisms by which Ephx2 may influence AS pathogenesis. CONCLUSION: By defining the AS network and corresponding RD, this study elucidated potential mechanisms by which Ephx2 affects AS through specific KEGG pathways, AOPs, and target genes. These findings enhanced the understanding of AS pathogenesis and highlighted potential targets like Mapk3 for developing therapeutic strategies in AS prevention and treatment.