Supplementary file 1_Honeybee venom therapy and viral infection: a systematic synthesis of venom antiviral activity.docx

The bioactive components of honeybee venom (HBV) have displayed broad evolutionary antiviral activity in animal models; however, there is limited evidence for the efficacy, indications, or side effects of the use of HBV in humans. We performed a systematic review and meta-analysis of the available preclinical and clinical evidence systematically assessing the antiviral efficacy and safety of HBV. A comprehensive search strategy for all studies reporting HBV in relation to direct-acting antiviral effects was performed through electronic databases from their inception up to October 2025. A total of 32 articles were identified for quantitative synthesis, with some included under meta-analysis. Although majority of the studies show high heterogeneity and limitations, the meta-analysis results provide encouraging evidence for the broad-spectrum antiviral property of HBV against numerous viruses, such as influenza viruses, herpes simplex virus, HIV, hepatitis viruses, and emerging coronaviruses. Mechanistically, the HBV components directly disrupt viral replication or do so via body immunomodulation pathways. The main adverse effects of HBV include dose-related cytotoxicity and mild allergic responses, with rare instances (less than 0.1%) of anaphylaxis. Overall, the antiviral roles of HBV are strongly supported in preclinical studies, although the clinical data on humans have limitations. Therefore, improving formulations and conducting safety assessment in future clinical practice, particularly through the use of nanocarriers or combined therapeutic strategies, may enhance the imperative HBV antiviral potency and reduce its limitations.