A functional genomics-pharmacotranscriptomics framework identifies host-directed anti-influenza agents.

Influenza A virus (IAV) remains a major threat to human and animal health, while the emergence of drug-resistant strains necessitates new antiviral strategies. Here, we developed an integrative host-directed drug discovery framework combining functional genomics and pharmacotranscriptomics. By aggregating published genome-wide screens, we assigned host genes functional scores reflecting their effects on IAV replication and used these scores to estimate the antiviral status of host cells. Screening nearly 20,000 drug-induced transcriptional signatures identified compounds that shift host gene expression toward an antiviral state. Among 54 selected hits, 18 showed anti-IAV activity. Notably, lithocholic acid and ALW-II-49-7 inhibited viral replication in vitro and protected mice from lethal infection in vivo. This host-targeted framework provides a systematic and scalable strategy for discovering antivirals that are less susceptible to resistance and potentially applicable to other rapidly evolving pathogens.