Epigenetic Regulation of the Epstein–Barr Virus Latent–Lytic Switch

Epstein-Barr virus (EBV) establishes lifelong latency in humans, yet sporadically reactivates into a productive lytic cycle that enables viral propagation. The lytic phase is critical for sustaining life-long persistence and also contributes to oncogenesis by fostering cellular environments that support EBV-associated malignancies. EBV lytic reactivation has long been understood as a complex process shaped by the integration of multiple, largely host-derived signals. Recent advances in genome-wide CRISPR screening, single-cell transcriptomics, and integrative multi-omic analyses have substantially expanded this framework, adding rich and unexpected molecular detail to how epigenetic repression, transcriptional control, metabolic adaptation, and immune-microenvironmental cues converge to regulate the latent-lytic 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.