An integrative meta-analysis of SARS-CoV-2 RNA–protein interactomes identifies conserved host factors shared with other RNA viruses

Abstract RNA viruses cause substantial global disease burden and depend on host RNA-binding proteins and translation machinery. However, it remains unclear which host factors are robustly engaged across independent Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) RNA interactome studies and to what extent these factors are shared with other RNA viruses. Here, we perform an integrative meta-analysis of eight published SARS-CoV-2 RNA–protein interactomes and compare them with corresponding Influenza A virus, Zika virus, and Dengue virus datasets to define conserved host networks and prioritize candidate host-directed antiviral targets. By integrating multiple datasets and applying ClusterProfiler together with curated pathway resources (KEGG, Reactome, WikiPathways, and Gene Ontology), we systematically characterize the functional landscape of SARS-CoV-2 RNA–protein interactions. The consensus SARS-CoV-2 interactome is enriched for mRNA processing, translation, RNA surveillance and innate immune functions. Cross-viral comparison identifies 275 host proteins shared across all four RNA viruses, forming interconnected modules that include key translation factors (EEF1A1, EIF4A1, EIF3H) and RNA-binding proteins (Nucleolin, ILF3). Drug–target annotation prioritizes 21 proteins with 35 approved or investigational modulators for host-directed antiviral repurposing. Together, these findings generate a consensus map of conserved host dependencies and highlight prioritized targets for future mechanistic and translational studies. Research Highlights Integrated SARS-CoV-2 datasets and compared with, Influenza A virus, Zika virus, Dengue virus. Identified 275 host proteins shared across these four pathogens. Conserved proteins were enriched in translation, RNA processing, and innate immune pathways. Prioritized 21 host targets and 35 drugs for antiviral repurposing.