Unveiling immune-metabolic interaction in Atherosclerosis via Comprehensive Landscape of Hub Genes and Immune Microenvironment

Objective: Atherosclerosis (AS) as a major cause of cardiovascular diseases, is considered a chronic inflammatory disease and accelerates by inflammation, lipid metabolism disorder and other mechanisms. AS pathogenesis and its relationship with immune regulation and metabolic interactions is still not fully elucidated. The purpose of this study is to delve into the correlation between mitochondrial metabolism and immunity in AS, and identify potential therapeutic targets for clinical treatment. Methods: Hub genes associated with mitochondrial metabolism and the pathogenesis of AS were identified by performing differentially expressed genes (DEGs) analysis and Weighted Gene Co-expression Network Analysis (WGCNA) based on two gene expression datasets (GSE100927 and GSE43292). And the biological processes and pathways of DEGs were determined through gene ontology (GO) and Gene Set Enrichment Analysis (GSEA) analysis. Then stepwise regression, random forest, and Lasso regression machine learning were used to evaluate the diagnostic value of hub genes. After that, the immune infiltration and single cell sequencing dataset GSE184073 were analyzed, and the immune cell composition in peripheral blood from AS patients using Mass Cytometry were detected to further consider the influence of immunoregulation. Results: Ten hub genes associated with mitochondrial metabolism and AS pathogenesis were identified, including NDUFS4, AIFM3, IDUA, TNF, CHKA, SLC11A1, SLC35C1, SLC37A2, ARSB, SLC16A5. GO and GSEA analysis showed their correlation with immunity and inflammation. Lasso regression revealed that TNF and ARSB had relatively good diagnostic performance. Further exploration was conducted on the expression of these hub genes in the immune microenvironment and their correlation with different immune factors. Mass cytometry demonstrated the influence of the vascular immune microenvironment on the pathogenesis of AS. Conclusions: Our study provides a more comprehensive understanding of the complex relationships between immune and metabolic factors and their impact on the microenvironment of AS. The identification of hub genes in AS may provide new targets for therapeutic intervention.