NSUN2-Mediated m5C Methylation in Human Disease: Mechanism and Therapeutic Implications

Abstract: The epitranscriptomic landscape defined by reversible post-transcriptional RNA modifications constitutes a sophisticated layer of gene regulatory circuitry that modulates diverse biological processes. As an essential writer enzyme for RNA 5-methylcytosine (m 5 C), NOP2/Sun RNA methyltransferase 2 (NSUN2) catalyzes site-specific m 5 C deposition across an extensive repertoire of cellular transcripts spanning messenger RNAs, transfer RNAs and non-coding RNAs, and orchestrates core post-transcriptional events including transcript stabilization, nucleocytoplasmic trafficking, translational tuning and RNA turnover. Accumulating preclinical and clinical evidence corroborates that perturbed NSUN2 expression rewires the physiological m 5 C epitranscriptomic signature, which functionally contributes to the onset and advancement of numerous human pathological conditions ranging from heterogeneous malignancies and cardiovascular complications to neurodegenerative syndromes, infectious disorders, inflammatory pathologies and systemic metabolic diseases. In this systematic review, we comprehensively consolidate contemporary mechanistic advances underlying NSUN2-dependent m 5 C modification in governing cellular homeostasis and disease pathogenesis, with focused discussion on its multifaceted functions in modulating oncogenic signaling cascades, mitochondrial fitness, neurodevelopmental progression, immune cell polarization and host-virus interaction. We further highlight prospective therapeutic modalities targeting the NSUN2–m 5 C regulatory axis and systematically dissect prevailing translational bottlenecks hindering bench-to-bedside transformation of such targeted interventions. Elucidating the conserved and disease-specific regulatory paradigms of NSUN2 therefore provides profound theoretical implications and practical clinical evidence for developing novel diagnostic biomarkers and precision therapeutic regimens across relevant human disorders. Keywords: NSUN2, 5-methylcytosine, RNA methylation, epitranscriptome, human disease, therapeutic target