Antiviral Mechanism of Gentiopicroside Against Herpes Zoster by Targeting TLR3

Herpes zoster (HZ), caused by the reactivation of human herpes virus 3 (HHV-3), is a painful neurological condition with limited treatment options. Gentiopicroside (GPS), a key iridoid compound from the traditional Chinese medicine Gentiana scabra, possesses broad anti-inflammatory and immunomodulatory properties, yet its potential against HHV-3 remains unexplored. Given the critical role of the Toll-like receptor 3 (TLR3) pathway in initiating antiviral innate immunity, this study aimed to investigate the anti-HHV-3 activity of GPS and its dependence on TLR3. We found that GPS treatment significantly reduced viral titers in HHV-3 infection in vitro. Mechanistically, GPS upregulated TLR3 expression and subsequently attenuated the HHV-3-induced production of pro-inflammatory cytokines TNF-α and IL-6. Furthermore, GPS ameliorated HHV-3-induced reduction in cell viability and attenuated apoptosis. Crucially, the antiviral efficacy of GPS was enhanced by a TLR3 agonist and diminished by a TLR3 inhibitor, demonstrating that its action is TLR3-dependent. In conclusion, our findings reveal that GPS exerts its anti-HHV-3 effects by modulating the TLR3-mediated immune response, highlighting its potential as a novel therapeutic candidate for herpes zoster.