Host-Directed Antiviral Strategies Against Influenza Viruses: Host Targets, Multi-Omics Approaches and AI-Assisted Discovery

Influenza viruses continue to pose a significant threat to both animal and public health due to their rapid evolution and the frequent emergence of antiviral resistance. Host-directed antiviral (HDA) strategies, which target host factors essential for viral replication, may represent an alternative to conventional virus-targeting approaches. However, the identification of reliable and therapeutically actionable host targets remains a major challenge, primarily due to the complexity and context dependency of host-virus interactions. Recent advancements in multi-omics technologies, including functional genomics, transcriptomics, and proteomics, have facilitated the systematic characterization of host factors involved in influenza virus infection. These methodologies have unveiled intricate regulatory networks that govern viral replication and host immune responses. Nonetheless, translating large-scale datasets into biologically meaningful targets necessitates robust integrative frameworks. In this context, artificial intelligence (AI) and machine learning methods offer powerful tools for data integration, target prioritization, and predictive modeling. In this Review, we summarize current insights into host factors that regulate influenza virus infection and discuss how multi-omics and AI-driven approaches are expediting host target discovery. Furthermore, we highlight the potential of these strategies to enhance antiviral development while addressing key challenges related to specificity, safety, and translational application. Collectively, these advancements lay a foundation that may support the rational design of next-generation host-directed antivirals.