Quercetin Restores Antiviral Innate Immunity by Blocking BVDV Npro-Hsp70-Mediated ELF4 Degradation

Bovine Viral Diarrhea Virus (BVDV) causes severe economic losses in the cattle industry, threatening both animal health and food security. Its nonstructural protein Npro suppresses type I interferon (IFN-I) responses, yet the underlying mechanism remains incompletely defined. Here, we reveal that BVDV Npro hijacks host heat shock protein 70 (Hsp70) to serve as a degradation adaptor for the transcription factor ELF4, promoting its K48-linked polyubiquitination and proteasomal degradation. ELF4 loss blunts IFN-I signaling, impairing antiviral cytokine production. Notably, the plant flavonoid quercetin, a known Hsp70 inhibitor, blocks this interaction, rescues ELF4 expression, and restores IFN-I responses in vitro and in vivo, leading to significant suppression of viral replication. Our findings uncover a new immune evasion axis and highlight the potential of natural compounds like quercetin in developing sustainable antiviral strategies for livestock health.