Exploring the Potential Association of Infectious Mononucleosis With Diffuse Large B‐Cell Lymphoma: A Mendelian Randomization and miRNA Profiling Approach

Diffuse large B‐cell lymphoma (DLBCL) is clinically heterogeneous malignancy with complex etiological factors. The role of Epstein‐Barr virus (EBV) infection, particularly infectious mononucleosis (IM), in DLBCL development remains controversial. This study aims to elucidate the potential mechanisms underlying the inverse association between IM and DLBCL by investigating the causal relationship between EBV and DLBCL using Mendelian randomization (MR) and comprehensive miRNA profiling. We employed a two‐sample MR approach to assess the causal effect of EBV infection on DLBCL risk, using genetic variants associated with IM and DLBCL from genome‐wide association studies (GWAS). miRNA profiling was performed on bulk RNA sequencing data from IM and DLBCL samples. Differential expression analysis, functional enrichment, and protein‐protein interaction (PPI) network analysis were conducted to identify key regulatory pathways and potential therapeutic targets. MR analysis demonstrated a potential inverse association between IM and DLBCL, with an odds ratio (OR) of 0.796 (95%CI: 0.635–0.999, p ‐value = 0.049). Differential miRNA expression analysis identified significant dysregulation in 146 miRNAs in IM and 328 miRNAs in DLBCL, with nine shared miRNAs suggesting overlapping regulatory pathways. Functional enrichment highlighted critical pathways such as autophagy and apoptotic signaling. The prognostic model successfully stratified patients into high‐ and low‐risk groups, significantly correlating with survival outcomes. Drug sensitivity analysis indicated increased responsiveness to targeted therapies in high‐risk patients. These findings suggest biological mechanisms that may underlie the observed inverse association between IM and DLBCL and provide candidate miRNAs for prognostic evaluation. Further validation in larger, multi‐ethnic cohorts with molecular subtyping is needed.