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

## TL;DR

This study finds that the ubiquitin–proteasome system (UPS) is linked to immune evasion and poor outcomes in EBV-related nasopharyngeal carcinoma, suggesting it could be a new target for treatment.

## Contribution

The study identifies EBV-regulated UPS-related genes as drivers of immune evasion and poor prognosis in EBV-associated nasopharyngeal carcinoma.

## Key findings

- 85 EBV-interacting differentially expressed genes were identified, with many linked to the ubiquitin–proteasome system (UPS).
- UPS-High cells showed reduced immune activation and increased stemness signaling, while UPS-Low cells had growth-promoting pathways.
- High UPS expression was associated with worse outcomes in pan-cancer and head and neck cancers, including nasopharyngeal carcinoma.

## Abstract

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.

The online version contains supplementary material available at 10.1038/s41598-025-34808-4.