Targeting host factors in antiviral therapy: new frontiers in combating viral infections

The rapid emergence of antiviral resistance and recurrent viral outbreaks have exposed limitations of conventional direct-acting antivirals (DAAs), prompting increasing interest in host-directed antiviral therapies (HDAs). Unlike virus-targeted agents, HDAs target host cellular factors and pathways required for viral replication, potentially providing broader activity and a higher genetic barrier to resistance. This review summarizes advances in host-targeted antiviral strategies and their therapeutic potential against established and emerging viral pathogens. We examine host dependency and restriction factors, together with virus-host interactions, as key therapeutic targets. Functional genomic approaches, including CRISPR-based screening and RNA interference (RNAi), have enabled systematic identification and modulation of host factors. We discuss CRISPR-mediated genome editing, RNAi therapeutics, metabolic reprogramming, and small-molecule host-targeting antivirals, highlighting their mechanisms, therapeutic development, and advantages over conventional approaches. Major challenges include host toxicity, pathway redundancy, delivery limitations, off-target effects, and viral adaptation. Emerging directions, including artificial intelligence-assisted target discovery, multi-omics integration, programmable nucleic acid therapeutics, and precision medicine, may accelerate the development of broad-spectrum and pandemic-ready antivirals. Overall, host-directed strategies represent a paradigm shift in antiviral drug development, offering opportunities for durable, potentially less susceptible to classical resistance mechanisms, and potentially broad-spectrum host-targeting approacheswhile complementing existing virus-directed therapies. Their successful translation will depend on identifying safe non-essential host targets, improving tissue-specific delivery, integrating combination therapies, and establishing robust safety and efficacy profiles for clinical use across diverse populations.