RNA N4-acetylcytidine modification in human cancers: from molecular function to oncogenic mechanisms

The RNA epitranscriptome represents a critical layer of gene regulation, with N4-acetylcytidine (ac4C) emerging as a pivotal modification in cancer biology. Catalyzed exclusively by N-acetyltransferase 10 (NAT10), ac4C decorates a broad spectrum of RNAs, profoundly influencing their stability and translation efficiency. This review synthesizes recent advances illuminating how the NAT10-ac4C axis drives oncogenic processes, including sustained proliferation, metabolic reprogramming, invasion and metastasis, immunosuppression, and therapy resistance by selectively stabilizing mRNAs encoding key oncoproteins. We detail the molecular mechanisms underpinning these roles across diverse malignancies, highlighting context-dependent functions and intricate cross-talk with other signal pathways. Furthermore, we explore the translational promise of this pathway, discussing NAT10 inhibitors and rational combination therapies that resensitize tumors to conventional treatments in preclinical models. Unraveling the full regulatory circuitry of ac4C will not only deepen our understanding of cancer pathogenesis but also pave the way for novel diagnostic and therapeutic strategies in precision oncology.