This study, published in *Nature* by a team from UC San Francisco and other institutions, aimed to identify human host factors essential for the replication of influenza A virus. Using a genome-wide RNAi screen in human lung epithelial cells, the researchers identified 295 cellular cofactors required for early-stage influenza virus replication. These factors were enriched in signaling pathways, ubiquitination, and phosphatase activity. The study also constructed a host-pathogen interaction network involving 181 confirmed host cellular factors and 4,266 interactions between viral and cellular proteins. Key findings included the identification of factors involved in viral entry, such as CD81, FGFR4, GSK3B, and v-ATPase subunits, and post-entry steps, including nuclear import components, proteases, and CAMK2B. The study further demonstrated that these host factors are essential for the replication of both wild-type influenza viruses and the 2009 swine-origin H1N1 influenza virus. The identification of these host factors provides new targets for antiviral drug development and highlights the potential for host factor-directed therapies to reduce the emergence of viral resistance.This study, published in *Nature* by a team from UC San Francisco and other institutions, aimed to identify human host factors essential for the replication of influenza A virus. Using a genome-wide RNAi screen in human lung epithelial cells, the researchers identified 295 cellular cofactors required for early-stage influenza virus replication. These factors were enriched in signaling pathways, ubiquitination, and phosphatase activity. The study also constructed a host-pathogen interaction network involving 181 confirmed host cellular factors and 4,266 interactions between viral and cellular proteins. Key findings included the identification of factors involved in viral entry, such as CD81, FGFR4, GSK3B, and v-ATPase subunits, and post-entry steps, including nuclear import components, proteases, and CAMK2B. The study further demonstrated that these host factors are essential for the replication of both wild-type influenza viruses and the 2009 swine-origin H1N1 influenza virus. The identification of these host factors provides new targets for antiviral drug development and highlights the potential for host factor-directed therapies to reduce the emergence of viral resistance.