<p>Influenza A virus (IAV) poses a significant threat to human health. The outcome of IAV results from the viral-host interaction, with the underlying molecular mechanisms largely unknown. By integrating the plasma proteomics data of the IAV-infected patients into the viral-inflammation protein-protein interaction (VI-PPI) network created in this study, purine nucleoside phosphorylase (PNP), the critical enzyme in purine salvage, was identified as a potential hub gene that connected the different stages of IAV infection. Extended survival rates and reduced pulmonary inflammatory lesions were observed in alveolar epithelial cell (AEC)-specific PNP conditional knockout mice upon H1N1 infection. Mechanistically, PB1-F2 of IAV was revealed as a novel viral transcriptional factor to bind to the TATA box of PNP promoter, leading to enhanced purine salvage in H1N1-challenged AECs. The activation of PNP-mediated purine salvage was verified in IAV-infected patients and A549 cells. PNP knockdown elicited a purine metabolic shift from augmented salvage pathway to de novo synthesis, constraining both viral infection and pro-inflammatory signaling through APRT-AICAR-AMPK activation. Moreover, durdihydroartemisinin (DHA), predicted by VI-PPI as a novel PNP inhibitor, exerted beneficial effects on the survival and weight gain of H1N1-challenged mice via its direct binding to PNP. To reveal for the first time, we found that PNP, activated by IAV, plays a hub role within H1N1-host interaction, simultaneously modulating viral replication and hyperinflammation through purine salvage. Our study sheds new light on a “two-for-one” strategy by targeting purine salvage in combating IAV-related pathology, suggesting PNP as a potential novel anti-influenza host target.</p><p></p>