Curcumin maintains pseudorabies virus latent infection by inhibiting the phosphorylation level of EGFR protein

Pseudorabies virus (PRV), a member of the herpesvirus family, establishes latent Infection in the host's peripheral nervous system and reactivates under stress conditions, causing disease. Curcumin (Cur) has been shown to exhibit anti-PRV activity; however, its role in regulating PRV reactivation remains unclear. Using PRV latency and dexamethasone (Dex)-reactivation models in PC-12 cells and mice, we demonstrated that Cur pretreatment suppressed lytic replication and reactivation, maintaining PRV in a latent state, as evidenced by upregulation of the latency-associated transcript (LAT), downregulation of the immediate-early gene IE180, and a reduction in viral genome copy numbers. Moreover, Cur suppressed Dex-induced reactivation and alleviated mitochondrial dysfunction and Apoptosis. Mechanistic experiments targeting EGFR signaling performed after latency was established (day 6 post-infection) revealed that Cur reduced both the expression of EGFR and its phosphorylation levels (p-EGFR). Through EGFR overexpression and knockdown experiments, we confirmed that EGFR acts as a key mediator through which Cur maintains PRV latency. Correlation analysis further revealed strong linear relationships between p-EGFR and apoptotic markers (Bax, Bcl-2, and apoptotic cell number), confirming that Cur suppresses Apoptosis and maintains latency via inhibition of EGFR phosphorylation. Furthermore, proteome-wide interaction analysis showed that EGFR-interacting proteins are enriched in pathways related to ribosomes, the spliceosome, and glycolysis/gluconeogenesis, suggesting the involvement of these pathways in the regulatory mechanism. This study is the first to demonstrate that Cur suppresses PRV productive replication and maintains latent Infection by inhibiting EGFR expression and phosphorylation, thereby providing a theoretical foundation for developing Cur-based interventions to control pseudorabies recrudescence in swine.