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

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. This study identifies NAT10-mediated RNA ac4C modification as a key regulator of colonic epithelial aging. Through N4-acetylation regulation of DYRK1A, NAT10 promotes intestinal senescence, highlighting a potential therapeutic target for elderly-onset colitis.