Epitranscriptomic modifications, such as N6-methyladenosine (m6A), are critical regulators of RNA metabolism, influencing gene expression, RNA stability, translation, and cellular responses to infection. Growing evidence indicates that these modifications and the enzymes responsible for their regulation play important roles in host–pathogen interactions, including viral replication and immune responses. However, the mechanisms by which RNA modifications influence viral infection and pathogenesis remain incompletely understood. Building on our recent findings published in Genome Research, which highlight the involvement of RNA-modifying enzymes in viral replication, this project aims to further characterize the role of epitranscriptomic regulation in host–virus interactions and explore its potential for antiviral therapeutic development. The project will combine functional genomics, high-throughput sequencing, computational biology, and molecular approaches to investigate epitranscriptomic regulation across different viral infection models and relevant cellular systems. Genome-wide screening approaches will be used to identify RNA-modifying enzymes and associated host factors involved in viral replication and cellular responses to infection. In parallel, next-generation sequencing will be employed to characterize infection-associated changes at the transcriptomic, epitranscriptomic, and epigenomic levels. A major computational component of the project will involve processing and analyzing large-scale sequencing datasets, genome-wide mapping and quantification, differential analyses, and integration of multiple layers of molecular information. Comparative analyses across experimental conditions and model systems will be used to identify conserved and context-dependent regulatory mechanisms. Candidate epitranscriptomic regulators identified through these analyses will be further investigated as potential therapeutic targets. Computational and structural approaches will support the prioritization of candidate proteins and the development of targeted therapeutic strategies, including targeted protein degradation approaches. Access to NAISS high-performance computing resources, including Arrhenius, will enable efficient and reproducible processing, analysis, and integration of large-scale genomic and epigenomic datasets and support computationally demanding downstream analyses. Overall, this project will advance our understanding of epitranscriptomic regulation during viral infection and provide a foundation for the development of innovative host-directed antiviral strategies relevant to both existing and emerging viral diseases.