Epitranscriptomic signatures of m5C, m6A, and pseudouridine in COVID-19 reveal host RNA modifications involved in viral pathogenesis

RNA modifications are increasingly recognized as critical regulators of host-virus interactions, yet their specific roles in human viral infections remain largely unexplored. Here, we provide the first comprehensive epitranscriptomic map of 5-methylcytosine (m5C), N6-methyladenosine (m6A), and pseudouridine (psU) in the host transcriptome during SARS-CoV-2 infection. By combining direct RNA sequencing with advanced modification-calling algorithms, we identify hundreds of condition-specific sites, reveal their positional preferences within transcripts, and uncover their functional association with immune defense and viral entry pathways. These findings demonstrate that host RNA modifications are dynamically remodeled during infection and define molecular signatures with potential diagnostic and therapeutic value. Our work establishes RNA modification profiling as a powerful tool for dissecting viral pathogenesis and opens new avenues for targeted antiviral strategies.