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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.<\/jats:p>","DOI":"10.1021\/acs.jafc.6c05625","type":"journal-article","created":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T13:06:08Z","timestamp":1785848768000},"page":"23543-23555","source":"Crossref","is-referenced-by-count":0,"title":["Quercetin Restores\nAntiviral Innate Immunity by Blocking\nBVDV Npro-Hsp70-Mediated ELF4 Degradation"],"prefix":"10.1021","volume":"74","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2277-6366","authenticated-orcid":true,"given":"Shanshan","family":"Liu","sequence":"first","affiliation":[{"name":"Heilongjiang Bayi Agricultural University , , ,","place":["Daqing, China, 163319"]},{"name":"Key Laboratory of Bovine Disease Control in Northeast China, Ministry of Agriculture and Rural Affairs , ,","place":["Daqing, China, 163319"]},{"name":"Engineering Research Center for Prevention and Control of Cattle Diseases , , ,","place":["Daqing, Heilongjiang Province, China, 163319"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nan","family":"Li","sequence":"additional","affiliation":[{"name":"Heilongjiang Bayi Agricultural University , , ,","place":["Daqing, China, 163319"]},{"name":"Key Laboratory of Bovine Disease Control in Northeast China, Ministry of Agriculture and Rural Affairs , ,","place":["Daqing, China, 163319"]},{"name":"Engineering Research Center for Prevention and Control of Cattle Diseases , , ,","place":["Daqing, Heilongjiang Province, China, 163319"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li","family":"Wang","sequence":"additional","affiliation":[{"name":"Heilongjiang Bayi Agricultural University , , ,","place":["Daqing, China, 163319"]},{"name":"Key Laboratory of Bovine Disease Control in Northeast China, Ministry of Agriculture and Rural Affairs , ,","place":["Daqing, China, 163319"]},{"name":"Engineering Research Center for Prevention and Control of Cattle Diseases , , ,","place":["Daqing, Heilongjiang Province, China, 163319"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ying","family":"Yu","sequence":"additional","affiliation":[{"name":"Heilongjiang Bayi Agricultural University , , ,","place":["Daqing, China, 163319"]},{"name":"Key Laboratory of Bovine Disease Control in Northeast China, Ministry of Agriculture and Rural Affairs , ,","place":["Daqing, China, 163319"]},{"name":"Engineering Research Center for Prevention and Control of Cattle Diseases , , ,","place":["Daqing, Heilongjiang Province, China, 163319"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu","family":"Liu","sequence":"additional","affiliation":[{"name":"Heilongjiang Bayi Agricultural University , , ,","place":["Daqing, China, 163319"]},{"name":"Key Laboratory of Bovine Disease Control in Northeast China, Ministry of Agriculture and Rural Affairs , ,","place":["Daqing, China, 163319"]},{"name":"Engineering Research Center for Prevention and Control of Cattle Diseases , , ,","place":["Daqing, Heilongjiang Province, China, 163319"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yulong","family":"Zhou","sequence":"additional","affiliation":[{"name":"Heilongjiang Bayi Agricultural University , , ,","place":["Daqing, China, 163319"]},{"name":"Key Laboratory of Bovine Disease Control in Northeast China, Ministry of Agriculture and Rural Affairs , ,","place":["Daqing, China, 163319"]},{"name":"Engineering Research Center for Prevention and Control of Cattle Diseases , , ,","place":["Daqing, Heilongjiang Province, China, 163319"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zecai","family":"Zhang","sequence":"additional","affiliation":[{"name":"Heilongjiang Bayi Agricultural University , , ,","place":["Daqing, China, 163319"]},{"name":"Key Laboratory of Bovine Disease Control in Northeast China, Ministry of Agriculture and Rural Affairs , ,","place":["Daqing, China, 163319"]},{"name":"Engineering Research Center for Prevention and Control of Cattle Diseases , , ,","place":["Daqing, Heilongjiang Province, China, 163319"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xue","family":"Wang","sequence":"additional","affiliation":[{"name":"Heilongjiang Bayi Agricultural University , , ,","place":["Daqing, China, 163319"]},{"name":"Key Laboratory of Bovine Disease Control in Northeast China, Ministry of Agriculture and Rural Affairs , ,","place":["Daqing, China, 163319"]},{"name":"Engineering Research Center for Prevention and Control of Cattle Diseases , , ,","place":["Daqing, Heilongjiang Province, China, 163319"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yaping","family":"Chen","sequence":"additional","affiliation":[{"name":"Heilongjiang Bayi Agricultural University , , ,","place":["Daqing, China, 163319"]},{"name":"Key Laboratory of Bovine Disease Control in Northeast China, Ministry of Agriculture and Rural Affairs , ,","place":["Daqing, China, 163319"]},{"name":"Engineering Research Center for Prevention and Control of Cattle Diseases , , ,","place":["Daqing, Heilongjiang Province, China, 163319"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shubo","family":"Wen","sequence":"additional","affiliation":[{"name":"Inner Mongolia Minzu University , , Inner Mongolia , ,","place":["Tongliao, China, 028000"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0993-9060","authenticated-orcid":true,"given":"Zhanbo","family":"Zhu","sequence":"additional","affiliation":[{"name":"Heilongjiang Bayi Agricultural University , , ,","place":["Daqing, China, 163319"]},{"name":"Key Laboratory of Bovine Disease Control in Northeast China, Ministry of Agriculture and Rural Affairs , ,","place":["Daqing, China, 163319"]},{"name":"Engineering Research Center for Prevention and 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Spectr."},{"key":"2026080510103234700_cit16","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2024.1288501","article-title":"SKping cell\ncycle regulation: role of ubiquitin ligase SKP2 in hematological malignancies","volume":"14","author":"William","year":"2024","journal-title":"Front. Oncol."},{"issue":"1","key":"2026080510103234700_cit17","doi-asserted-by":"publisher","first-page":"68","DOI":"10.1158\/1541-7786.MCR-19-0187","article-title":"ELF4\nIs a Target of miR-124 and Promotes Neuroblastoma Proliferation and\nUndifferentiated State","volume":"18","author":"Kosti","year":"2020","journal-title":"Mol. Cancer Res."},{"issue":"11","key":"2026080510103234700_cit18","doi-asserted-by":"publisher","DOI":"10.3390\/v14112365","article-title":"Quercetin Inhibits Hsp70 Blocking of Bovine Viral Diarrhea Virus\nInfection and Replication in the Early Stage of Virus Infection","volume":"14","author":"Chen","year":"2022","journal-title":"Viruses"},{"issue":"1","key":"2026080510103234700_cit19","doi-asserted-by":"publisher","first-page":"266","DOI":"10.1002\/ptr.7309","article-title":"Quercetin\nand its derivates as antiviral potentials: A comprehensive review","volume":"36","author":"Di Petrillo","year":"2022","journal-title":"Phytother. Res."},{"issue":"1","key":"2026080510103234700_cit20","doi-asserted-by":"publisher","DOI":"10.1186\/s12985-024-02299-w","article-title":"Quercetin inhibits\nSARS-CoV-2 infection\nand prevents syncytium formation by cells co-expressing the viral\nspike protein and human ACE2","volume":"21","author":"Roy","year":"2024","journal-title":"Virol J."},{"issue":"1","key":"2026080510103234700_cit21","doi-asserted-by":"publisher","DOI":"10.3390\/v8010006","article-title":"Quercetin as an Antiviral\nAgent Inhibits Influenza A Virus (IAV)\nEntry","volume":"8","author":"Wu","year":"2016","journal-title":"Viruses"},{"issue":"1","key":"2026080510103234700_cit22","doi-asserted-by":"publisher","DOI":"10.1007\/s40203-022-00132-2","article-title":"Quercetin\nattenuates viral infections by interacting with target proteins and\nlinked genes in chemicobiological models","volume":"10","author":"Rahman","year":"2022","journal-title":"In\nSilico Pharmacol."},{"issue":"7","key":"2026080510103234700_cit23","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.00530-20","article-title":"Quercetin\nBlocks Ebola Virus Infection by Counteracting the VP24 Interferon-Inhibitory\nFunction","volume":"64","author":"Fanunza","year":"2020","journal-title":"Antimicrob. Agents Chemother."},{"key":"2026080510103234700_cit24","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2021.727254","article-title":"PD-1 Blockade Restores\nthe Proliferation\nof Peripheral Blood Lymphocyte and Inhibits Lymphocyte Apoptosis in\na BALB\/c Mouse Model of CP BVDV Acute Infection","volume":"12","author":"Liu","year":"2021","journal-title":"Front. Immunol."},{"issue":"4","key":"2026080510103234700_cit25","doi-asserted-by":"publisher","DOI":"10.3390\/ijms23042372","article-title":"Identification\nof Nifurtimox and Chrysin as Anti-Influenza Virus Agents by Clinical\nTranscriptome Signature Reversion","volume":"23","author":"Xin","year":"2022","journal-title":"Int. J. Mol.\nSci."},{"issue":"12","key":"2026080510103234700_cit26","doi-asserted-by":"publisher","first-page":"1237","DOI":"10.1038\/ni.2756","article-title":"ELF4 is critical for induction of\ntype I interferon and the host antiviral response","volume":"14","author":"You","year":"2013","journal-title":"Nat. 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Comp. Immunol."},{"issue":"11","key":"2026080510103234700_cit36","doi-asserted-by":"publisher","DOI":"10.3390\/biology14111480","article-title":"The Biological\nFunctions\nand Mode of Action of Transcription Factor ELF4: A Promising Target\nfor Treating Intestinal Homeostasis Disorder-Related Diseases","volume":"14","author":"Xie","year":"2025","journal-title":"Biology"},{"key":"2026080510103234700_cit37","doi-asserted-by":"publisher","first-page":"151","DOI":"10.1016\/j.rvsc.2022.04.011","article-title":"Research advances on\ninterferon (IFN) response during BVDV infection","volume":"149","author":"Song","year":"2022","journal-title":"Res. Vet. Sci."},{"key":"2026080510103234700_cit38","doi-asserted-by":"publisher","DOI":"10.1016\/j.phymed.2023.154977","article-title":"Liang-Ge-San\ninhibits\ndengue virus serotype 2 infection by reducing caveolin1-induced cytoplasmic\nheat shock protein 70 translocation into the plasma membrane","volume":"119","author":"Chen","year":"2023","journal-title":"Phytomedicine"},{"issue":"12","key":"2026080510103234700_cit39","doi-asserted-by":"publisher","DOI":"10.3390\/v14122686","article-title":"Molecular\nMechanism and Role of Japanese Encephalitis Virus Infection in Central\nNervous System-Mediated Diseases","volume":"14","author":"Yadav","year":"2022","journal-title":"Viruses"},{"issue":"6","key":"2026080510103234700_cit40","doi-asserted-by":"publisher","DOI":"10.3390\/microorganisms11061473","article-title":"New Insights into the Role and Therapeutic Potential of Heat Shock\nProtein 70 in Bovine Viral Diarrhea Virus Infection","volume":"11","author":"Chen","year":"2023","journal-title":"Microorganisms"},{"key":"2026080510103234700_cit41","doi-asserted-by":"publisher","DOI":"10.3389\/fvets.2022.992678","article-title":"Bovine viral\ndiarrhea virus in China: A comparative genomic and phylogenetic analysis\nwith complete genome sequences","volume":"9","author":"Shah","year":"2022","journal-title":"Front. Vet.\nSci."},{"issue":"7","key":"2026080510103234700_cit42","doi-asserted-by":"publisher","first-page":"4957","DOI":"10.1007\/s11033-020-05641-x","article-title":"Investigation of the role of quercetin as a heat shock\nprotein inhibitor on apoptosis in human breast cancer cells","volume":"47","author":"K\u0131yga","year":"2020","journal-title":"Mol. Biol. Rep."},{"key":"2026080510103234700_cit43","doi-asserted-by":"publisher","DOI":"10.1016\/j.isci.2026.115704","article-title":"Quercetin Potentially\nSuppresses HBV Activity through Targeting the RIG-I\/MAVS Pathway","volume":"29","author":"Yang","year":"2026","journal-title":"iScience"},{"issue":"1","key":"2026080510103234700_cit44","doi-asserted-by":"publisher","DOI":"10.1186\/s13567-025-01455-6","article-title":"IFN-\u03b2 production induced by\nPRRSV is affected by GP3 quantity control and CLND4 interaction","volume":"56","author":"Li","year":"2025","journal-title":"Vet Res."},{"issue":"4","key":"2026080510103234700_cit45","doi-asserted-by":"publisher","first-page":"456","DOI":"10.1016\/j.jmii.2017.01.005","article-title":"Anti-apoptotic activity\nof Japanese encephalitis virus NS5 protein in human medulloblastoma\ncells treated with interferon-\u03b2","volume":"51","author":"Weng","year":"2018","journal-title":"J. Microbiol.\nImmunol. 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