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<p>Intestinal aging characterized by imbalance between cell senescence and mucosal self-renewal, increases susceptibility to the elderly-onset ulcerative colitis (UC), while the underlying mechanisms remain elusive. Here, we identify mRNA N4-acetylcytidine (ac<sup>4</sup>C) modification and its specific writer, N-acetyltransferase 10 (NAT10), as critical regulators of human colonic epithelial cell senescence. Knockdown of NAT10 significantly alleviates human colonic epithelial cell senescence in vitro and colonoid and intestinal aging in vivo in aged mice. Using ac<sup>4</sup>C-modified transcriptome sequencing, we reveal that NAT10 stabilizes <i>DYRK1A</i> mRNA through ac<sup>4</sup>C modification, thereby driving colon epithelial senescence. Moreover, NAT10 and DYRK1A are markedly upregulated in ulcerative colitis tissues from elderly patients and positively correlate with disease severity. Knockdown of NAT10, treatment with Nat10 or Dyrk1a inhibitor, alleviates colitis in aged mice. Collectively, these findings suggest that modulating NAT10-mediated RNA ac<sup>4</sup>C modification could rejuvenate intestinal aging and provide a novel therapeutic strategy for elderly-onset colitis.</p>

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Targeting NAT10 alleviates colonic senescence and elderly-onset colitis by disrupting N4-acetylation of DYRK1A

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年3月1日

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  • Jingyu Chen,
  • Meng Xue,
  • Shuyi Mi,
  • Anbo Fu,
  • Wenwen Chen,
  • Yuhao Sun,
  • Shenglong Xia,
  • Qiwei Ge,
  • Jiakai Luo,
  • Qiao Yu,
  • Liangjing Wang,
  • Shujie Chen

摘要

Intestinal aging characterized by imbalance between cell senescence and mucosal self-renewal, increases susceptibility to the elderly-onset ulcerative colitis (UC), while the underlying mechanisms remain elusive. Here, we identify mRNA N4-acetylcytidine (ac4C) modification and its specific writer, N-acetyltransferase 10 (NAT10), as critical regulators of human colonic epithelial cell senescence. Knockdown of NAT10 significantly alleviates human colonic epithelial cell senescence in vitro and colonoid and intestinal aging in vivo in aged mice. Using ac4C-modified transcriptome sequencing, we reveal that NAT10 stabilizes DYRK1A mRNA through ac4C modification, thereby driving colon epithelial senescence. Moreover, NAT10 and DYRK1A are markedly upregulated in ulcerative colitis tissues from elderly patients and positively correlate with disease severity. Knockdown of NAT10, treatment with Nat10 or Dyrk1a inhibitor, alleviates colitis in aged mice. Collectively, these findings suggest that modulating NAT10-mediated RNA ac4C modification could rejuvenate intestinal aging and provide a novel therapeutic strategy for elderly-onset colitis.