Emerging role of N-acetyltransferase 10 in diseases: RNA ac4C modification and beyond.

Abstract

N⁴-acetylcytidine (ac4C), a conserved RNA modification, plays critical roles in RNA stability and translation. As the primary enzyme catalyzing ac4C, N-acetyltransferase 10 (NAT10) is increasingly implicated in diverse diseases. This review systematically explores NAT10's multifaceted contributions to cancer, autoimmune disorders, infectious diseases, cardiovascular conditions, and metabolic syndromes. In cancer, NAT10 drives malignancy by enhancing oncogenic processes such as proliferation, metastasis, and therapy resistance, with overexpression linked to poor prognosis across multiple malignancies. Beyond oncology, NAT10 dysregulation is associated with autoimmune diseases like rheumatoid arthritis and systemic lupus erythematosus, where it modulates immune responses through RNA acetylation. In infectious contexts, NAT10 influences sepsis progression and viral pathogenesis by stabilizing pathogen-related RNAs, while in cardiovascular diseases, it exacerbates myocardial injury and heart failure through ac4C-dependent and independent pathways. Additionally, NAT10 promotes metabolic dysfunction-associated steatotic liver disease by regulating lipid metabolism genes. The review further discusses therapeutic strategies targeting NAT10, including small-molecule inhibitors and gene silencing approaches, which show promise in preclinical models by suppressing tumor growth, enhancing chemosensitivity, and mitigating inflammatory damage. By integrating molecular insights and clinical relevance, this work underscores NAT10 as a pivotal regulator of disease mechanisms and a potential target for future therapeutic interventions. Future research should address context-dependent roles, refine ac4C detection methods, and explore combinatorial therapies to overcome resistance mechanisms.