Epstein-Barr virus (EBV) is a ubiquitous human herpesvirus that establishes lifelong latency in its host and is associated with a range of malignancies and immune-related disorders. This review examines the complex interactions between EBV and microRNAs (miRNAs), small, non-coding RNAs that regulate gene expression at the post-transcriptional level. It focuses on EBV-encoded miRNAs derived from the BHRF1 and BART clusters, detailing their distinct functions during different latency phases and viral reactivation. These miRNAs facilitate immune evasion, modulate cell cycle progression, apoptosis, and differentiation, and promote cellular environments that favor viral persistence and oncogenesis. EBV also disrupts host miRNA networks, altering gene expression and immune regulation, which contributes to tumor development in diseases such as Burkitt's lymphoma, nasopharyngeal carcinoma, Hodgkin's lymphoma, and post-transplant lymphoproliferative disorders, and has additionally emerged as a leading etiological factor in multiple sclerosis. Furthermore, the review highlights how viral and host miRNAs jointly modulate immune checkpoints, antiviral defense mechanisms, and the tumor microenvironment. It concludes by summarizing recent progress in miRNA-based diagnostics and therapeutics, underscoring their potential for advancing personalized medicine in EBV-associated pathologies.

Biochemistry and Molecular Biology Department Faculty of Pharmacy Al Azhar University Nasr City Cairo 11231 Egypt

Department of Biochemistry Faculty of Pharmacy and Drug Technology Egyptian Chinese University Cairo 11786 Egypt

Department of Biochemistry Faculty of Pharmacy Badr University in Cairo Badr City Cairo 11829 Egypt

Department of Botany Faculty of Science Mansoura University Mansoura 35516 Egypt

Department of Medical Analysis Technology Faculty of Applied Health Sciences Technology Badr University in Cairo Cairo Egypt

Department of Pharmacology College of Medicine University of Bisha Bisha 61922 Saudi Arabia

Molecular Biology and Biotechnology Department School of Biotechnology Badr University in Cairo Badr City Cairo 11829 Egypt

Pharmacology and Toxicology Department Faculty of Pharmacy Badr University in Cairo Badr City Cairo 11829 Egypt

School of Biotechnology Badr University in Cairo Badr City Cairo 11829 Egypt

Zoology and Entomology Department Faculty of Science Helwan University Helwan Egypt

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