RNA N4‐acetylcytidine modification and its role in health and diseases

Abstract N4‐acetylcytidine (ac4C) modification is a crucial RNA modification widely present in eukaryotic RNA. Previous studies have demonstrated that ac4C plays a pivotal role in viral infections. Despite numerous studies highlighting the strong correlation between ac4C modification and cancer progression, its detailed roles and molecular mechanisms in normal physiological processes and cancer progression remain incompletely understood. This review first outlines the key regulatory enzyme mediating ac4C modification, N‐acetyltransferase 10 (NAT10), including its critical roles in regulating RNA stability, transcriptional efficiency, and translational fidelity. Additionally, it systematically summarizes the essential functions and mechanisms of ac4C modification in normal biological processes, including stem cell fate determination, spermatogenesis and oogenesis, embryonic development, cellular senescence, and bone remodeling. Furthermore, this review delves into the central roles and molecular mechanisms of ac4C modification in regulating malignant proliferation, cell cycle arrest, EMT, drug resistance, cell death, cancer metabolism, and tumor immunotherapy. It also emphasizes the potential of NAT10 as a prognostic biomarker and its therapeutic potential as a target for disease treatment. In summary, this review clarifies the multifaceted roles of ac4C modification in both health and disease and explores NAT10‐targeted therapies with the aim of advancing cancer research and improving patient outcomes.