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<p>RNA modifications represent a fundamental layer of epitranscriptomic regulation. Among them, <i>N</i><sup>4</sup>-acetylcytidine (ac<sup>4</sup>C)—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/ac<sup>4</sup>C 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 ac<sup>4</sup>C 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/ac<sup>4</sup>C signaling drives diverse pathological states. In cancer, aberrant ac<sup>4</sup>C 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/ac<sup>4</sup>C axis not merely as an RNA-modifying pathway, but as a dynamic, disease-relevant integrator at the intersection of epitranscriptomics, immunity, and metabolism.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年3月5日

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  • Caiyun Shang,
  • Xiaoxue Wang,
  • Yanling Huang,
  • Jingyi Zhu,
  • Xueqian Liu,
  • Heng Zhang,
  • Wuxiang Guan,
  • Haojie Hao,
  • Fang Zhang

摘要

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.