Enterovirus A71 (EV‐A71) is a highly contagious virus that poses a major threat to global health, representing the primary etiological agent for hand–foot and mouth disease (HFMD) and neurological complications. It has been established that interferon signaling is critical to establishing a robust antiviral state in host cells, mainly mediated through the antiviral effects of numerous interferon‐stimulated genes (ISGs). The host restriction factor SHFL is a novel ISG with broad antiviral activity against various viruses through diverse underlying molecular mechanisms. Although SHFL is widely acknowledged for its broad‐spectrum antiviral activity, it remains elusive whether SHFL inhibits EV‐A71. In this work, we validated that EV‐A71 triggers the upregulation of SHFL both in cell lines and in a mouse model. Knockdown and overexpression of SHFL in EVA71‐infected cells suggested that this factor could markedly suppress EV‐A71 replication. Our findings further revealed an intriguing mechanism of SHFL that it could interact with the nonstructural proteins 3Dpol of EV‐A71 and promoted the degradation of 3Dpol through the ubiquitin–proteasome pathway. Furthermore, the zinc‐finger domain and the 36 amino acids (164–199) of SHFL were crucial to the interaction between SHFL and EV‐A71 3Dpol. Overall, these findings broadened our understanding of the pivotal roles of SHFL in the interaction between the host and EV‐A71.

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