The ubiquitin-proteasome system is an important driver of EBV-associated nasopharyngeal carcinoma progression: a...

Epstein-Barr virus (EBV)-associated nasopharyngeal carcinoma (NPC) is characterized by extensive immune infiltration, yet immune evasion remains a hallmark. In this study, we aimed to leverage publicly available datasets to identify EBV-host gene interactions and re-map their expression at single-cell resolution. We conducted a meta-analysis to identify differentially expressed genes, mapped these genes to EBV-host interaction data, constructed a network, and performed pathway enrichment. Single-cell RNA sequencing datasets were used to map these genes at cellular resolution. We analysed differences in cell cycle, immune signaling, cell-cell interactions, and assessed prognostic associations of UPS signature using the GEPIA2 platform. We identified 85 EBV-interacting DEGs regulated by lytic-phase proteins. Clustering highlighted genes related to the ubiquitin-proteasome system (UPS). Single-cell analyses confirmed elevated UPS-related gene expression in NPC. UPS-High cells exhibited lower proliferative activity, enriched stemness signaling, and reduced antigen presentation and immune activation, whereas UPS-Low cells showed marked upregulation of growth-promoting pathways. High UPS expression was associated with poorer outcomes in pan-cancer, head and neck squamous cell carcinoma, and marginally significant in the small NPC datasets. The proportion of UPS-High cells varied widely across patients. UPS activity, influenced by EBV lytic proteins, is linked to immune evasion, stemness, proliferation, and adverse prognosis. These findings support UPS as a potential biomarker and therapeutic target in NPC, warranting validation and functional studies.