Multi-Omics Profiling Reveals Capsaicin Suppresses EBV Lytic Reactivation in Epithelial Cancers by Targeting Viral and Host Regulatory Networks.

Epstein-Barr virus (EBV) lytic reactivation contributes to the pathogenesis of EBV-associated epithelial malignancies, including nasopharyngeal carcinoma and gastric carcinoma, highlighting the need for therapeutic strategies targeting viral reactivation. Capsaicin exhibits anticancer and antiviral activities; however, its effects on EBV lytic reactivation remain unclear. This study investigated the effects of capsaicin on EBV lytic reactivation in EBV-positive epithelial cancer models. Capsaicin significantly suppressed the expression of lytic genes, including BZLF1, BRLF1, BMRF1, and BLLF1, and reduced EBV virion production. Proteomic analysis revealed alterations in host cellular pathways associated with metabolism, chromatin organization, and cytoskeletal regulation, whereas metabolomic profiling demonstrated perturbations in nucleotide, amino acid, and polyamine metabolism processes involved in viral DNA replication and protein synthesis. Protein-protein interaction network analysis identified key host proteins, including HSP90AB1, MYH9, and ANXA2, implicated in metabolic reprogramming, cytoskeletal organization, and stress responses. Moreover, upstream regulators associated with EBV lytic activation, including p65, AP-1, HIF-1α, and SP1, were down-regulated following capsaicin treatment. Collectively, these findings demonstrate a multitarget inhibitory effect of capsaicin on EBV lytic reactivation and support its therapeutic potential against EBV-associated epithelial malignancies.