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In this study, it is revealed that the host E3 ubiquitin ligase FBXO5 suppresses viral replication by mediating NSP7 lysine\u201048\u2010linked ubiquitination and subsequent proteasomal degradation. Interestingly, it is also determined that NSP7 expression impairs the host antiviral response by inhibiting the ISGylation of melanoma differentiation\u2010associated protein 5 (MDA5), a key sensor for viral RNA. Through an unbiased esiRNA screen, it is identified that NSP7 ubiquitination is coregulated by \u03b2\u2010TrCP1 and the kinase TAF1. Additionally, this study uncovers a small molecule FBXO5 stabilizer that disrupts the \u03b2\u2010TrCP1\u2013FBXO5 interaction, thereby markedly enhancing NSP7 degradation and effectively mitigating SARS\u2010CoV\u20102 infection. 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