Integrated Bioinformatics Analysis identifying Key Regulators of Metabolic and Immune Signaling in EBV-Associated Diffuse Large B-Cell Lymphoma

Abstract

Epstein–Barr virus (EBV) is a well-established oncogenic virus associated with several lymphoid malignancies including diffuse large B-cell lymphoma (DLBCL). However, the molecular mechanisms underlying EBV-driven DLBCL remain incompletely understood. This study aimed to identify shared molecular signatures and key regulatory genes linking EBV infection and DLBCL through integrated bioinformatics analyses. Three Gene Expression Omnibus (GEO) datasets comprising of EBVtransformed B cells, DLBCL patients and EBV-positive DLBCL samples were analyzed. A total of 487 common differentially expressed genes (DEGs) were identified across all datasets. Functional enrichment analysis revealed significant involvement of p53, MAPK, cytokine–cytokine receptor interaction, viral response and immune regulatory pathways. Protein–protein interaction network analysis identified ICAM1, CXCR4, FYN, IRF4 and PECAM1 as key hub genes. GeneMANIA analysis linked these genes to leukocyte migration, lymphocyte differentiation, interferon-γ response and cell adhesion. Immune infiltration analysis demonstrated strong associations between key genes, diverse immune cell populations and immune checkpoint molecules. GSEA further revealed activation of oxidative phosphorylation, TCA, proteasome, ubiquitin-mediated proteolysis, mTOR, TLR and RIG-I-like receptor signaling pathways in EBV-positive DLBCL. Drug enrichment analysis identified dexamethasone, tretinoin, rosiglitazone and mangiferin as potential therapeutic candidates. Collectively, these findings highlight novel biomarkers, therapeutic targets and molecular mechanisms involved in EBV-associated DLBCL.