Platycodin D Restricts NDV Replication via modulation of MAPK, NLRP3 Inflammasome and Interferon Signaling

Newcastle disease (ND), caused by Newcastle disease virus (NDV), remains a major threat to the global poultry industry. Long-term use of live attenuated vaccines may contribute to the persistence of NDV in the field, as well as the emergence of viral mutations and atypical infections. These limitations highlight the urgent need for effective antiviral agents against NDV. In this study, we investigated the antiviral activity of Platycodin D (PD) against NDV and elucidated its underlying host-targeted mechanisms. PD significantly inhibited NDV replication both in vitro and in vivo, resulting in reduced viral loads and attenuated tissue injury in infected chickens. Transcriptomic profiling combined with network pharmacology analysis identified inflammation-, apoptosis-, and interferon-related pathways as major targets of PD, with MAPK signaling emerging as a central regulatory node. Mechanistic studies demonstrated that PD suppressed NDV-induced activation of the MAPK pathway and NLRP3 inflammasome assembly, leading to decreased production of pro-inflammatory cytokines, including IL-1β, IL-6, IL-8, and IL-18. In parallel, PD attenuated virus-induced apoptosis through upregulation of the anti-apoptotic protein Bcl-2. Moreover, PD enhanced antiviral innate immunity by promoting type I interferon (IFN-α/β) expression and STAT1 phosphorylation. Collectively, these findings indicate that PD restricts NDV infection by coordinately modulating host inflammatory, apoptotic, and innate antiviral signaling pathways, supporting its potential as a host-targeted antiviral candidate for the control of Newcastle disease.