The NAT10/ac4C axis: bridging RNA epigenetics to human diseases

N4-acetylcytidine (ac4C) stands as the sole RNA acetylation mark identified to date in eukaryotes, dynamically installed by N-acetyltransferase 10 (NAT10). This modification has been linked to mRNA stability and translation, and its dysregulation is increasingly implicated in human pathologies. This review synthesizes current knowledge on the discovery, distribution, and deposition of ac4C, with a focus on its writer, NAT10. We discuss the roles of ac4C in safeguarding tRNA decoding fidelity, modulating RNA metabolism, and cellular stress responses. Furthermore, we systematically examine the expanding landscape of NAT10/ac4C dysfunction in cancer, cardiovascular diseases, metabolic disorders, infectious diseases, immune-mediated inflammatory conditions, and nervous system diseases. By examining current limitations, we propose key directions for future investigation, including the development of advanced detection tools and targeted therapeutic strategies. We suggest that the NAT10/ac4C axis may constitute a signaling cascade hub, maintaining homeostasis under physiological conditions and translating persistent stress signals into disease-specific phenotypes under pathological conditions. This framework will provide a conceptual basis for translating ac4C biology into clinical applications.