Abstract
<title>Abstract</title> <p>Background Coronary heart disease (CHD) and non-alcoholic fatty liver disease (NAFLD) are highly prevalent metabolic disorders that share pathological characteristics, including chronic inflammation, immune dysregulation, and metabolic dysregulation. However, the shared molecular mechanisms and immune microenvironment characteristics underlying CHD and NAFLD comorbidity remain poorly understood. Methods Transcriptomic and single-cell RNA sequencing (scRNA-seq) datasets related to CHD and NAFLD were obtained from the Gene Expression Omnibus (GEO) database. Differential expression analysis, weighted gene co-expression network analysis (WGCNA), functional enrichment analysis, immune infiltration analysis, and cell–cell communication analysis were performed to identify shared hub genes and potential pathogenic mechanisms between the two diseases. In addition, RT-qPCR and Western blot assays were conducted in ox-LDL-induced vascular smooth muscle cells and OA/PA-induced hepatocyte models to validate the expression of key genes in vitro. Results A total of 37 shared downregulated module genes were identified between CHD and NAFLD, among which FOXO1, SIK1, IER3, BIRC3, and NUPR1 were recognized as hub genes. Functional enrichment analyses demonstrated that these genes were primarily involved in inflammation- and immunity-related pathways, including NF-κB, TNF, IL-17, and chemokine signaling pathways. Immune infiltration and scRNA-seq analyses revealed significant alterations in monocyte/macrophage populations in both diseases, while BIRC3, SIK1, and IER3 were predominantly expressed in macrophages. CellChat analysis further uncovered extensive ligand–receptor interactions among disease-associated cell populations, suggesting that dysregulated immune cell–cell communication may contribute to the shared pathogenic progression of CHD and NAFLD. Moreover, RT-qPCR and Western blot analyses consistently confirmed the downregulated expression patterns of FOXO1, SIK1, IER3, BIRC3, and NUPR1 in disease models. Conclusions This study revealed shared immune–metabolic dysregulation between CHD and NAFLD through integrated multi-omics and single-cell analyses and identified FOXO1, SIK1, IER3, BIRC3, and NUPR1 as shared hub genes. These findings provide novel insights into the comorbidity mechanisms linking CHD and NAFLD and may contribute to the identification of potential therapeutic targets.</p>