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  • Targeting Epstein–Barr Virus-Induced Oncogenic Pathways Using Natural Polyphenols: Therapeutic Potential of EGCG and Resveratrol

  • Sogand Karami,1,*
    1. Faculty of Veterinary Medicine, Semnan University, Semnan, Iran


  • Introduction: Epstein–Barr virus (EBV), a ubiquitous oncogenic gamma-herpesvirus infecting more than 90% of the global population, is strongly associated with several malignancies, including Burkitt lymphoma, Hodgkin lymphoma, nasopharyngeal carcinoma, and a subset of gastric cancers. EBV establishes lifelong latent infection through coordinated expression of viral proteins such as Epstein–Barr nuclear antigen 1 (EBNA1) and latent membrane protein 1 (LMP1), which promote malignant transformation by stimulating cell proliferation, inhibiting apoptosis, facilitating immune evasion, and activating oncogenic signaling pathways including NF-κB, JAK/STAT, and PI3K/Akt. In addition, EBV contributes to genetic and epigenetic alterations that sustain tumor progression. Although chemotherapy, radiotherapy, and targeted therapies have improved clinical outcomes, treatment resistance, systemic toxicity, and tumor recurrence remain major challenges. Consequently, naturally derived bioactive compounds have gained increasing attention as complementary therapeutic candidates. Among them, epigallocatechin-3-gallate (EGCG), the principal catechin of green tea, and resveratrol, a polyphenolic stilbene found in grapes and berries, possess antiviral, antioxidant, anti-inflammatory, and anticancer activities that may interfere with EBV-induced oncogenesis through multiple molecular mechanisms.
  • Methods: A systematic literature search was performed using PubMed, Scopus, and Web of Science databases for studies published between 2015 and 2025. Search terms included “Epstein–Barr virus,” “EBV-associated malignancies,” “EBV-induced oncogenesis,” “EGCG,” “resveratrol,” “polyphenols,” “viral oncogenesis,” and “natural anticancer compounds.” Eligible studies included in vitro, in vivo, and clinical investigations evaluating the molecular or therapeutic effects of EGCG and resveratrol in EBV-associated cancers. Studies lacking mechanistic evidence or unrelated to virus-associated malignancies were excluded. The selected literature was qualitatively analyzed according to molecular targets, antiviral activity, anticancer mechanisms, and translational potential.
  • Results: Current evidence indicates that EGCG and resveratrol interfere with EBV-induced oncogenesis by targeting both viral oncogenic proteins and host signaling networks involved in malignant transformation. EGCG has been reported to modulate EBNA1-related functions and suppress the expression of viral genes involved in both latent and lytic infection, thereby limiting viral persistence. Furthermore, EGCG inhibits NF-κB and STAT3 activation, attenuates oxidative stress, promotes apoptosis, and may regulate epigenetic processes through modulation of DNA methylation-associated enzymes, collectively suppressing tumor-promoting pathways. Resveratrol primarily targets cellular pathways activated by EBV. Experimental studies suggest that it suppresses LMP1-mediated signaling, inhibits NF-κB, PI3K/Akt, and JAK/STAT pathways, reduces inflammatory cytokine production, and induces mitochondrial apoptosis through caspase-dependent mechanisms. In addition, resveratrol downregulates anti-apoptotic proteins, including survivin and Mcl-1, and may increase the sensitivity of EBV-positive tumor cells to conventional chemotherapeutic agents. The complementary molecular mechanisms of EGCG and resveratrol suggest potential synergistic therapeutic effects through simultaneous disruption of viral latency, oncogenic signaling, oxidative stress, and apoptosis resistance. Nevertheless, both compounds exhibit limited oral bioavailability, rapid metabolic degradation, and insufficient tissue accumulation, restricting their clinical application. Advanced drug-delivery strategies, including polymeric nanoparticles, liposomes, and other nanocarrier systems, may improve pharmacokinetic performance and enhance therapeutic efficacy.
  • Conclusion: Natural polyphenols, particularly EGCG and resveratrol, represent promising complementary therapeutic candidates for EBV-associated malignancies by targeting viral latency, oncogenic signaling pathways, oxidative stress, inflammation, apoptosis, and epigenetic dysregulation. Their multitarget mechanisms distinguish them from conventional single-target therapies and support their potential role in precision oncology. Future research should focus on standardized formulations, biomarker-guided patient selection, combination strategies with existing anticancer therapies, and nanotechnology-based delivery systems to improve bioavailability and accelerate clinical translation for patients with EBV-associated cancers.
  • Keywords: Epstein–Barr virus; EGCG; Resveratrol; Natural polyphenols; Viral oncogenesis

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