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The lytic phase is critical for sustaining life\u2010long persistence and also contributes to oncogenesis by fostering cellular environments that support EBV\u2010associated malignancies. EBV lytic reactivation has long been understood as a complex process shaped by the integration of multiple, largely host\u2010derived signals. Recent advances in genome\u2010wide CRISPR screening, single\u2010cell transcriptomics, and integrative multi\u2010omic analyses have substantially expanded this framework, adding rich and unexpected molecular detail to how epigenetic repression, transcriptional control, metabolic adaptation, and immune\u2013microenvironmental cues converge to regulate the latent\u2013lytic transition. This review synthesizes recent discoveries that refine our understanding of the molecular logic of EBV reactivation and discusses how these insights are shaping new therapeutic approaches.<\/jats:p>","DOI":"10.1002\/jmv.71031","type":"journal-article","created":{"date-parts":[[2026,6,25]],"date-time":"2026-06-25T12:26:58Z","timestamp":1782390418000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Epigenetic Regulation of the Epstein\u2013Barr Virus Latent\u2013Lytic Switch"],"prefix":"10.1002","volume":"98","author":[{"given":"Rui","family":"Guo","sequence":"first","affiliation":[{"name":"Department of Molecular Biology and Microbiology Tufts University School of Medicine Boston Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benjamin E.","family":"Gewurz","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Infectious Diseases Mass General Brigham 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