NAT10-mediated RNA N4-acetylation promotes intestinal fibroblast senescence via DHRS2

Intestinal fibroblast senescence contributes to gut aging and the development of related diseases, yet the regulatory mechanisms governing this process remain largely elusive. In this study, we identify the RNA N4-acetylcytidine (ac⁴C) modification and its cognate writer, N-acetyltransferase 10 (NAT10), as key modulators of human colonic fibroblast senescence. Through a series of loss- and gain-of-function assays, we demonstrate that NAT10-mediated mRNA ac⁴C modification is functionally involved in controlling intestinal fibroblast senescence. Suppression of this modification diminishes senescence-associated markers and attenuates replicative, oxidative (H₂O₂), and DNA damage-induced (doxorubicin) senescence in intestinal fibroblasts. Mechanistically, NAT10-driven ac⁴C deposition enhances DHRS2 mRNA stability, thereby promoting fibroblast senescence. Collectively, our findings establish the NAT10/ac⁴C/DHRS2 regulatory axis as a critical player in intestinal fibroblast senescence and suggest its potential as a therapeutic target for age-related intestinal disorders.