The Novel Viral Non‐Coding RNA LMP2A‐IT1 Promotes the Lytic Replication of EBV

The Epstein-Barr virus (EBV) is recognized as the first human tumor virus and etiologically linked to a spectrum of malignancies and autoimmune diseases. EBV lytic replication contributes substantially to pathogenesis, but the viral components that enable efficient replication within host cells remain incompletely understood. Here, we identified a previously unknown EBV non-coding RNA (ncRNA) from glycoRNA samples and designated it LMP2A-IT1. This viral ncRNA was consistently detected across multiple EBV-infected cell lines, in exosomes, and in EBV-positive nasopharyngeal carcinoma tissues, exhibiting a predominantly cytoplasmic distribution. Functional analyses reveal that the induction of LMP2A-IT1 during EBV lytic replication actively drives the lytic cycle, resulting in a self-amplifying positive feedback loop. Mechanistically, LMP2A-IT1 appears to activate an inflammatory response, which subsequently upregulates BZLF1, a master regulator of the EBV lytic cascade, to facilitate lytic progression. Together, our findings suggest that LMP2A-IT1 represents a previously unrecognized viral factor that EBV deploys to achieve robust replication. To our best knowledge, this is the first report of a viral RNA harboring glycosylation modifications, thereby expanding the glycoRNA landscape. Moreover, this study offers new mechanistic insights into EBV replication as well as a potential biomarker and therapeutic target for EBV-associated diseases.