Broad-spectrum antivirals (BSAs) possess unique advantages of being effective against a wide range of both existing and unpredictable emerging viral infections. The host type I interferon (IFN) response serves as a universal defense against diverse viral infections nonspecifically, providing attractive targets to develop novel BSAs. In this study, we identified the flavonoid kaempferide as an enhancer of the type I IFN activated Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathway, promoting the expression of IFN stimulated genes (ISGs) and the establishment of cellular antiviral status. Additionally, our study clearly demonstrated that kaempferide exhibits potent BSA activity against diverse viruses including the highly pathogenic severe fever with thrombocytopenia syndrome virus (SFTSV) and Crimean-Congo hemorrhagic fever virus (CCHFV), by synergizing with either endogenous or exogenous IFNs. Mechanistic study further revealed that kaempferide acts by preventing the suppressor of cytokine signaling 3-mediated negative feedback, prolonging the duration of type I IFN stimulated JAK/STAT signaling. In summary, we herein report kaempferide as a novel potential BSA agent that deserves further development in the future.
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