Fei-Yan-Qing-Hua decoction inhibits influenza viral replication by enhancing NK cell maturation and activation through the upregulation of JAK/STAT/T-bet signalling axis.

The main obstacle of influenza is that only a small proportion of cases progress to severe disease due to massive viral replication and excessive immune responses, while effective therapeutics for influenza-induced pneumonia are urgently needed. This study elucidates the protection of Fei-Yan-Qing-Hua decoction (FYQHD), a traditional Chinese medicine, against lethal influenza A virus (IAV) infection in murine models. NK cell depletion experiments showed that NK cells might play an important role during the protection of FYQHD against influenza. FYQHD enhances phosphorylation of the JAK/STAT pathway, leading to the upregulation of transcription factors as T-bet, etc., which promotes NK cell maturation and activation, and then markedly increases the expression of NKG2D, IFN-γ and perforin. Meanwhile, FYQHD upregulates the expression of chemokine receptors CCR2/3/6 on NK cells via JAK/STAT axis, thereby facilitating their chemotaxis towards the lungs. Importantly, the main bioactive compounds glabridin and naringenin show affinity to IL-2Rα, while ursolic acid binds to STAT5. Collectively, FYQHD suppresses viral replication by promoting the number and function of NK cells in lungs during the initial period of influenza. This provides a mechanistic foundation for the clinical application of FYQHD and highlights the translational potential of its active components, underscoring the value of traditional Chinese medicine in the treatment of influenza.