Introduction Pseudorabies virus (PRV), a significant pathogen of swine, causes substantial economic losses, and even poses an emergent public health concern due to its zoonotic potential. The continuous evolution of PRV has undermined the effectiveness of current vaccines and antiviral drugs. Consequently, there is an urgent need to develop novel strategies to curb its spread. Methods The inhibitory effect of garcinone C on PRV replication was assessed in vivo and in vitro . To determine the stage of antiviral action, treatments were administered at different time points: pre-treatment, co-treatment, and post-infection. RNA sequencing was performed, and differentially expressed genes (DEGs) were identified. Results In the study, we found that garcinone C inhibited PRV replication in a concentration- and timedependent manner in vitro. The antiviral activity of garcinone C was specific to post-infection administration and did not extend to pre-treatment and cotreatment conditions. Transcriptomic analysis identified DEGs between garcinone C- and vehicle-treated cells after PRV infection. KEGG pathway enrichment analysis of the DEGs indicated that the antiviral effect of garcinone C was primarily associated with the PI3K-Akt signaling pathway, potentially through the downregulation of the host epidermal growth factor. Furthermore, garcinone C suppressed the production of key inflammatory cytokines such as IL-6, IL-8, and TNF-a during PRV infection. Oral administration of garcinone C conferred protection in PRVinfected mice, leading to attenuated weight loss, an improved survival rate, as well as reduced pathological changes and viral loads in tissues. Discussion Collectively, our findings identify garcinone C as a promising therapeutic candidate against PRV and elucidate its underlying molecular mechanism.
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