Abstract
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.
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Data availability
The RNA-seq data generated in this study have been deposited in the SRA database under accession code PRJNA1394239 (https://www.ncbi.nlm.nih.gov/sra/?term=PRJNA1394239). The acRIP-seq data generated in this study have been deposited in the SRA database under accession code PRJNA1347399 (https://www.ncbi.nlm.nih.gov/sra/?term=PRJNA1347399). Other data from the findings of this study are available from the corresponding author upon request. Source data are provided in this paper.
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Acknowledgements
We thank Xiaoyu Li (Zhejiang University School of Medicine) and Liang Lu (Zhejiang University) for their helpful discussions and technical support in the detection and analysis of RNA modifications. We thank Chunchun Li, Xiaoye Li, Liya Lin and Jiaying Li (Clinical Research Center, The Second Affiliated Hospital of Zhejiang University School of Medicine) for the laboratory management and technical support. We thank Yunlu Chen, Hui Xie and Zhenlin Jiang (Animal Experiment Center, The Second Affiliated Hospital of Zhejiang University School of Medicine) for their technical support in small animal endoscopy techniques. This project was financially supported by the National Foundation of Natural Science of China (82525010 to S.C.) and the Provincial Key R&D Program of Zhejiang (2023C03163 to L.W.).
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S.C., L.W., and M.X. designed and supervised the study. J.C. performed most experiments with the assistance of S.M., A.F., W.C., Y.S., S.X., Q.G., J.L., and Q.Y.; J.C. and M.X. analyzed and interpreted the data. J.C. drafted the manuscript. S.C. and L.W. critically revised the manuscript.
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Chen, J., Xue, M., Mi, S. et al. Targeting NAT10 alleviates colonic senescence and elderly-onset colitis by disrupting N4-acetylation of DYRK1A. Nat Commun (2026). https://doi.org/10.1038/s41467-026-70220-w
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DOI: https://doi.org/10.1038/s41467-026-70220-w
