The miRNA-virus Axis in RNA Virus Infections: Mechanisms, Therapeutic Targeting, and Systems Biology Approaches

RNA viruses are a diverse and rapidly evolving group of pathogens that significantly contribute to worldwide morbidity and mortality, propelled by elevated mutation rates and effective use of host cellular mechanisms. MicroRNAs (miRNAs) have emerged as an essential post-transcriptional regulator of host-virus interactions, influencing viral replication, immunological responses and disease progression. This review offers a comprehensive overview of the miRNA-virus axis in RNA virus infections, highlighting the dynamic and context-dependent roles of host miRNAs. We investigate the mechanistic basis of miRNA-mediated regulation, including direct targeting of viral RNA, modulation of host dependency factors, regulation of antiviral signaling pathways, and immune-mediated effects on infection outcomes. We propose a functional categorization of miRNAs that transcends the conventional antiviral-proviral dichotomy, facilitating a more accurate comprehension of their involvement in various infection settings. This review connects mechanistic insights with translational applications by outlining novel treatment techniques, such as miRNA mimics, anti-miRs, RNA interference, and CRISPR-based methodologies. We also propose a therapeutic decision framework that links miRNA functional classification with targeted antiviral interventions. Key challenges including delivery efficiency, tissue specificity, and off-target effects are also discussed, with emphasis on lipid nanoparticles and exosome-based delivery systems. We further highlight the role of systems biology approaches, including multi-omics integration, single-cell and spatial transcriptomics, network analysis, and artificial intelligence, in identifying regulatory miRNA hubs and enabling precision antiviral medicine. Collectively, this review reinterprets the miRNA-virus axis as a dynamic regulatory network and provides a translational framework for the development of next-generation antiviral therapeutics.