NAT10 inhibition alleviates renal tubular epithelial cell senescence by impeding ac4C acetylation of PAPP-A mRNA in diabetic nephropathy

  • Cell Death Dis. 2026 Jun 11. doi: 10.1038/s41419-026-08970-0.
Mingyang Hu  1  2  3  4 ,  Linxiao Lv  1  2  3  4 ,  Ruxu Li  2  4 ,  Zihao Zhao  2  4 ,  Wenxin Li  1  2  3 ,  Yanyan Wang  1  2  3 ,  Zhangsuo Liu  5  6  7  8 ,  Yanfang Lu  9  10  11  12 ,  Sijie Zhou  13  14  15  16
Affiliations
  • 1. Department of Nephrology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
  • 2. Research Institute of Nephrology, Zhengzhou University, Zhengzhou, China.
  • 3. Traditional Chinese Medicine Integrated Department of Nephrology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
  • 4. Tianjian Laboratory of Advanced Biomedical Sciences, Academy of Medical Sciences, Zhengzhou University, Zhengzhou, China.
  • 5. Department of Nephrology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China. [email protected].
  • 6. Research Institute of Nephrology, Zhengzhou University, Zhengzhou, China. [email protected].
  • 7. Traditional Chinese Medicine Integrated Department of Nephrology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China. [email protected].
  • 8. Tianjian Laboratory of Advanced Biomedical Sciences, Academy of Medical Sciences, Zhengzhou University, Zhengzhou, China. [email protected].
  • 9. Department of Nephrology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China. [email protected].
  • 10. Research Institute of Nephrology, Zhengzhou University, Zhengzhou, China. [email protected].
  • 11. Traditional Chinese Medicine Integrated Department of Nephrology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China. [email protected].
  • 12. Tianjian Laboratory of Advanced Biomedical Sciences, Academy of Medical Sciences, Zhengzhou University, Zhengzhou, China. [email protected].
  • 13. Department of Nephrology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China. [email protected].
  • 14. Research Institute of Nephrology, Zhengzhou University, Zhengzhou, China. [email protected].
  • 15. Traditional Chinese Medicine Integrated Department of Nephrology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China. [email protected].
  • 16. Tianjian Laboratory of Advanced Biomedical Sciences, Academy of Medical Sciences, Zhengzhou University, Zhengzhou, China. [email protected].
PMID: 42276981 DOI: 10.1038/s41419-026-08970-0
Abstract

Cellular senescence plays a critical role in diabetic nephropathy (DN). 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.A schematic diagram illustrates the multifaceted role of the NAT10 in renal tubular epithelial cell senescence upon type 1 and type 2 diabetic insult and the protective effect of targeting NAT10. NAT10 is currently recognized as the sole "writer" enzyme responsible for catalyzing the ac4C modification. The present study demonstrated that NAT10 is predominantly expressed in renal tubule and highly expressed in DN and correlated with renal tubular epithelial cell senescence. NAT10-mediated ac4C modification enhanced the expression of PAPP-A, which may directly influence senescence signaling by interacting with the key mediator p53, thereby promoting senescence signaling and renal tubular epithelial cell senescence. The aforementioned pathogenic pathways contribute to diabetic renal tubular cell injury in both type 1 and type 2 diabetes and can be mitigated by targeting NAT10, either genetically through conditional knockout (cKO) or adeno-associated virus-mediated knockdown, or pharmacologically using small-molecule inhibitors such as Remodelin.

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