RNA Modification Enzyme NAT10 Drives Gut Aging and Colitis in Elderly Patients

Aging of the intestinal epithelium — marked by cellular senescence, weakened barrier function, and impaired stem cell renewal — is increasingly recognized as a contributor to the rising incidence of ulcerative colitis (UC) in people over 60. Yet the molecular mechanisms linking gut epithelial aging to inflammation remain poorly understood. This study addresses that gap by identifying the RNA modification enzyme NAT10 and its downstream target DYRK1A as central regulators of colonic senescence.

The researchers first established that mRNA N4-acetylcytidine (ac4C) modification — a chemical mark added by NAT10 — is consistently elevated in senescent human colonic epithelial cells (NCM460 and CCD841 lines) induced by hydrogen peroxide, doxorubicin, or replicative exhaustion. NAT10 protein itself was progressively upregulated in mouse colonic tissue from 2 to 18 months of age, correlating with rising senescence markers (p53, p21, p16, γ-H2AX) and inflammatory SASP cytokines (IL-1β, IL-6, TNF-α).

To map which mRNAs NAT10 acetylates, the team performed ac4C-modified transcriptome sequencing (acRIP-seq). DYRK1A emerged as a top hit: NAT10 adds ac4C marks to the DYRK1A coding sequence, stabilizing the transcript and boosting DYRK1A protein expression. DYRK1A in turn phosphorylates and activates p21, locking cells in senescence. Knockdown of NAT10 reduced ac4C on DYRK1A mRNA, decreased DYRK1A and p21 levels, restored proliferation, and reduced SA-β-galactosidase positivity. Critically, a catalytically dead NAT10 mutant (NAT10-MUT) could not rescue senescence, confirming the effect is ac4C-dependent.

In vivo experiments in aged (12–18 month) mice showed that Nat10 heterozygous knockout (Nat10+/−) preserved colonic mucosal height, Ki67+ proliferating cells, Muc2+ goblet cells, and tight junction protein Occludin, while reducing senescence markers. Human colonoids derived from elderly donors and treated with a NAT10 inhibitor (Remodelin) or a DYRK1A inhibitor similarly showed reduced senescence and improved epithelial renewal. In a DSS-induced colitis model in aged mice, treatment with Remodelin or the DYRK1A inhibitor EGCG significantly attenuated weight loss, colon shortening, histological damage, and inflammatory cytokine production compared to controls.

Clinically, both NAT10 and DYRK1A were markedly elevated in colonic biopsies from elderly UC patients compared to younger UC patients or healthy elderly controls, and their expression correlated positively with endoscopic and histological disease severity scores. These findings collectively establish the NAT10→ac4C-DYRK1A→p21 axis as a conserved driver of intestinal epithelial aging and a promising, pharmacologically accessible target for elderly-onset UC.