The ubiquitin–proteasome system is an important driver of EBV-associated nasopharyngeal carcinoma progression: a meta-analysis of transcriptomic data

Abstract Background Epstein–Barr virus (EBV)-associated nasopharyngeal carcinoma (NPC) is characterized by extensive immune infiltration, yet immune evasion remains a hallmark of the disease. 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. Methods We conducted a meta-analysis of transcriptomic datasets to identify differentially expressed genes in NPC, mapped these genes to EBV–host interaction data, and constructed a network. Network clustering and pathway enrichment were performed, and 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 a 12-gene UPS signature using the GEPIA2 platform. Results We identified 85 EBV-interacting DEGs, most regulated by lytic-phase proteins. MCODE clustering highlighted genes related to the ubiquitin–proteasome system (UPS). Single-cell analyses confirmed elevated UPS-related gene expression in NPC compared to EBV-negative oropharyngeal cancer. 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. Survival analysis revealed that high UPS expression was associated with poorer outcomes in both pan-cancer and head and neck squamous cell carcinoma datasets. The proportion of UPS-High cells varied widely across patients. Conclusion 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 EBV-associated NPC, warranting NPC-specific validation and functional studies. Graphical Abstract EBV-driven ubiquitin–proteasome dysregulation in nasopharyngeal carcinoma revealed by bulk and single-cell transcriptomics, linked to immune evasion and poor survival.