N-Acetyltransferase 10 (NAT10) at the crossroads of metabolism, immunology, and cancer biology.

The multi-functional protein N-acetyltransferase 10 (NAT10), highly conserved from bacteria to human, is a versatile enzyme with an N-acetyltransferase domain, an RNA helicase domain, and a tRNA-binding domain, known for its ability to acetylate proteins and multiple RNA species. Specifically, NAT10 was reported to catalyze the N4-acetylcytidine (ac4C) modification on tRNA, rRNA, mRNA, and even viral RNA and to regulate translation efficiency, RNA stability, and eventually gene expression. NAT10 draws increasing attention for its emerging roles in rewiring metabolism, including amino acid, lipid, and glucose metabolism, and modulating immune responses to drive cancer progression, metastasis, and therapeutic resistance. In this review, we provide a conceptual framework of how the dysfunction of the highly conserved NAT10 leads to tumorigenesis, metastasis, and therapeutic resistance. We also summarize the major findings that reveal how NAT10 regulates cancer metabolism and immune responses. Lastly, we review the opportunities and challenges of targeting NAT10 to treat cancer and overcome drug resistance.