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  • Plant-Derived Berberine and Artesunate as Emerging Therapeutic Candidates Against Human Herpesvirus 8-Driven Kaposi Sarcoma: Molecular Mechanisms and Translational Perspectives

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


  • Introduction: Human herpesvirus 8 (HHV-8), also known as Kaposi sarcoma-associated herpesvirus (KSHV), is an oncogenic gamma-herpesvirus and the etiological agent of Kaposi sarcoma (KS), primary effusion lymphoma, and multicentric Castleman disease. KSHV establishes lifelong latency and promotes malignant transformation through viral proteins including latency-associated nuclear antigen (LANA), viral FLICE inhibitory protein (vFLIP), viral cyclin (vCyclin), and viral G protein-coupled receptor (vGPCR). These factors manipulate host signaling networks involved in cell survival, proliferation, inflammation, and angiogenesis, particularly NF-κB, PI3K/Akt/mTOR, and MAPK pathways. Although antiretroviral therapy, chemotherapy, and targeted treatments have improved clinical management, recurrence, treatment resistance, and disease-associated immunosuppression remain important challenges. Consequently, naturally derived compounds with multitarget anticancer activity have attracted increasing attention. Among these, berberine, an isoquinoline alkaloid found in several medicinal plants, and artesunate, a semisynthetic derivative of the sesquiterpene lactone artemisinin, represent promising candidates because of their reported antiviral, anti-inflammatory, pro-apoptotic, and antitumor activities.
  • Methods: A systematic literature search was conducted using PubMed, Scopus, and Web of Science for studies published between 2015 and 2025. Search terms included “HHV-8,” “KSHV,” “Kaposi sarcoma,” “berberine,” “artesunate,” “artemisinin,” “viral oncogenesis,” and “natural anticancer compounds.” Eligible studies included in vitro, in vivo, and translational investigations evaluating the molecular effects of berberine or artesunate on viral infection, cancer-associated signaling, cellular proliferation, apoptosis, oxidative stress, or angiogenesis. Studies lacking mechanistic evidence or unrelated to KSHV-associated malignancies were excluded. Evidence was qualitatively evaluated according to molecular targets, anticancer mechanisms, antiviral activity, and translational potential.
  • Results: Berberine and artesunate demonstrate complementary pharmacological properties that may be relevant to KSHV-associated oncogenesis. Berberine has been extensively investigated for its ability to regulate cancer-associated signaling pathways, including NF-κB, PI3K/Akt, AMPK, and MAPK. Through modulation of these pathways, berberine may suppress inflammatory signaling, cellular proliferation, and survival while promoting apoptosis. Because KSHV oncogenic proteins such as vFLIP and vGPCR activate overlapping signaling networks, targeting these host pathways represents a potentially relevant strategy for limiting virus-driven tumor progression. Artesunate provides a mechanistically distinct approach. Its anticancer activity has been associated with oxidative stress generation, mitochondrial dysfunction, apoptosis, and, in experimental cancer models, ferroptosis-related mechanisms. These properties may be particularly relevant to metabolically active and therapy-resistant tumor cells. Artesunate has also demonstrated antiviral and antitumor activity in experimental systems involving herpesviruses, supporting further investigation of its potential against KSHV-associated malignancies. The complementary mechanisms of berberine and artesunate provide a rationale for investigating combination strategies. Berberine could primarily modulate inflammatory and survival signaling, whereas artesunate could enhance oxidative and apoptotic stress within malignant cells. Such a dual-target strategy may theoretically interfere with multiple components of KSHV-driven tumor biology, including proliferation, survival, inflammation, and angiogenesis. However, direct evidence demonstrating synergistic activity of these compounds specifically against KSHV-associated cancers remains limited and requires experimental validation. Important translational barriers also remain, including variable pharmacokinetics, limited bioavailability, potential off-target effects, and insufficient clinical evidence. Nanocarrier-based formulations may represent a future strategy for improving stability, tissue distribution, and tumor-directed delivery of these compounds.
  • Conclusion: Berberine and artesunate represent promising plant-derived therapeutic candidates with complementary molecular activities relevant to KSHV-driven oncogenesis and Kaposi sarcoma. Their ability to modulate inflammatory and survival pathways, oxidative stress, apoptosis, and potentially angiogenic processes provides a mechanistic basis for further investigation. Nevertheless, current evidence should be interpreted primarily as preclinical, and direct therapeutic efficacy against KSHV-associated malignancies remains to be established. Future studies should focus on KSHV-specific experimental models, mechanistic validation, combination-based approaches, optimized drug-delivery systems, and clinical evaluation to determine whether these compounds can contribute to precision therapeutic strategies for KSHV-associated cancers.
  • Keywords: HHV-8; Kaposi sarcoma; Berberine; Artesunate; Viral oncogenesis

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