Epstein-Barr virus (EBV) is a key oncogenic driver of nasopharyngeal carcinoma (NPC) and is closely associated with cisplatin resistance, but its roles in metabolic reprogramming and chemoresistance remain unclear. This study aimed to investigate the role of EBV in polyamine metabolic reprogramming and its underlying mechanism in mediating cisplatin resistance in NPC. Metabolomic and Metabolic Flux Analysis confirmed that EBV significantly enhances polyamine anabolism in NPC cells, with ODC1, the rate-limiting enzyme of polyamine biosynthesis, transcriptionally upregulated by EBV-BZLF1 via direct binding to its promoter. Functional experiments revealed that the ODC1-spermidine axis promotes EBV replication and cell proliferation via eIF5A hypusination by upregulating EBV-EAD and host TRAF1, respectively, and induces B-to-Z DNA transition to attenuate cGAS-STING-mediated innate immune responses. Clinically, high ODC1 expression was an independent prognostic marker for poor survival in NPC patients. In vitro and in vivo, ODC1 knockdown or pharmacological inhibition with DFMO effectively restored cisplatin sensitivity in EBV-positive NPC cells, likely by reducing Z-DNA formation and potentiating cisplatin-induced innate immune responses. Collectively, our findings identify a novel EBV-ODC1-polyamine regulatory axis that promotes viral replication and confers a survival advantage to cancer cells, highlighting ODC1 as a promising therapeutic target to improve cisplatin efficacy in EBV-positive NPC.
Keywords: Epstein‐Barr virus; cisplatin resistance; eIF5A hypusination; innate immune responses; nasopharyngeal carcinoma; ornithine decarboxylase 1; polyamine metabolism.
PMID: 42603298
PMCID: PMC13477251
DOI: 10.1002/advs.77204
