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Understanding the mechanisms underlying the senescence response is therefore essential for developing effective therapies for DN. In this study, we provide evidence that NAT10 expression was markedly elevated in the kidney tissues of patient with DN and was associated with adverse clinical outcomes. NAT10 directly bound to PAPP-A, induced ac4C acetylation modification of the PAPP-A transcript, and enhanced its stability, thereby promoting PAPP-A upregulation. Moreover, NAT10-mediated ac4C acetylation accelerated renal tubular epithelial cell senescence in DN through the PAPP-A\/p53 pathway. Conditional knockout (cKO) of NAT10 attenuates renal tubular senescence in streptozotocin (STZ)-induced type 1 diabetes mellitus (T1DM) mouse models. Renal tubular-specific knockdown of NAT10 via targeted adeno-associated virus ameliorates renal tubular epithelial cell senescence in db\/db mouse models of type 2 diabetes mellitus (T2DM). Pharmacological inhibition of NAT10 with Remodelin protects against renal tubular epithelial cell senescence both in vivo and in vitro. In conclusions, NAT10-mediated ac4C acetylation contributes to renal tubular epithelial cell senescence in DN and that NAT10-regulated PAPP-A could be a promising and feasible therapeutic target in DN.<\/jats:p>","DOI":"10.1038\/s41419-026-08970-0","type":"journal-article","created":{"date-parts":[[2026,6,11]],"date-time":"2026-06-11T05:22:59Z","timestamp":1781155379000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["NAT10 inhibition alleviates renal tubular epithelial cell senescence by impeding ac4C acetylation of PAPP-A mRNA in diabetic nephropathy"],"prefix":"10.1038","volume":"17","author":[{"given":"Mingyang","family":"Hu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Linxiao","family":"Lv","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruxu","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zihao","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenxin","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanyan","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2916-8371","authenticated-orcid":false,"given":"Zhangsuo","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3545-8842","authenticated-orcid":false,"given":"Yanfang","family":"Lu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9219-0969","authenticated-orcid":false,"given":"Sijie","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,6,11]]},"reference":[{"key":"8970_CR1","doi-asserted-by":"publisher","first-page":"377","DOI":"10.1038\/s41581-020-0278-5","volume":"16","author":"JB Cole","year":"2020","unstructured":"Cole JB, Florez JC. 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