The NAT10/ac4C axis: a central nexus linking RNA acetylation to immunometabolic signaling in disease

RNA modifications represent a fundamental layer of epitranscriptomic regulation. Among them, N4-acetylcytidine (ac4C)—a highly conserved and functionally versatile mark deposited by N-acetyltransferase 10 (NAT10)—has recently emerged as a critical coordinator of immunometabolic homeostasis. In this review, we synthesize current evidence establishing the NAT10/ac4C axis as a central signaling hub that integrates immune regulation and metabolic control through post-transcriptional modulation of key transcripts. We summarize mechanistic advances demonstrating how ac4C shapes innate and adaptive immunity—including macrophage polarization, T cell activation, and B cell responses—while concurrently directing metabolic programs across glucose, lipid, and amino acid pathways via effects on RNA stability and translation. We further highlight convergent immunometabolic mechanisms by which dysregulated NAT10/ac4C signaling drives diverse pathological states. In cancer, aberrant ac4C activity promotes tumor-intrinsic growth, immunosuppressive microenvironment remodeling, and metabolic rewiring. Similar NAT10-linked immunometabolic circuits underlie autoimmune diseases, sepsis, and metabolic inflammatory disorders. Finally, we evaluate the landscape of NAT10 inhibitors and discuss opportunities for mechanism-guided therapeutic exploration. Together, this review positions the NAT10/ac4C axis not merely as an RNA-modifying pathway, but as a dynamic, disease-relevant integrator at the intersection of epitranscriptomics, immunity, and metabolism.