KAT2A-mediated H3K79 succinylation promotes ferroptosis in diabetic nephropathy by regulating SAT2

  • Life Sci. 2025 Sep 1:376:123746. doi: 10.1016/j.lfs.2025.123746.
Qunyong Peng  1 ,  Hanyong Zhang  2 ,  Zhenyu Li  3
Affiliations
  • 1. Department of Geriatric Medicine, Xiangya Hospital, Central South University, Changsha 410008, China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha 410008, China.
  • 2. Hunan Key Laboratory of The Research and Development of Novel Pharmaceutical Preparations, Changsha Medical University, Provincial first-class applied discipline (pharmacy), Changsha 410000, China.
  • 3. Department of Geriatric Medicine, Xiangya Hospital, Central South University, Changsha 410008, China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha 410008, China. Electronic address: [email protected].
PMID: 40409584 DOI: 10.1016/j.lfs.2025.123746
Abstract

Background: Diabetic nephropathy (DN) remains difficult to treat due to its complex mechanisms. This study explores the Ferroptosis mechanism in DN, focusing on the regulation of SAT2 expression by KAT2A-mediated H3K79 succinylation (H3K79succ).

Methods: A DN rat model was created using streptozotocin (STZ) and a high-fat diet (HFD). KAT2A expression in rat kidney tissue was analyzed by RT-qPCR, WB, and immunohistochemistry. Renal pathology and function were assessed, and Ferroptosis markers (ROS, GSH, MDA, and iron content) were measured. A high-glucose-induced HPo cell model was used for in vitro validation. KAT2A knockdown and CUT&Tag/RNA-seq were used to identify potential targets, and the regulation of SAT2 by KAT2A was confirmed through RT-qPCR, WB, and ChIP-qPCR.

Results: Elevated KAT2A and H3K79succ expression were observed in DN rat kidney tissues and HPo cells. KAT2A knockdown reversed kidney damage, improved renal function, and suppressed inflammation and Ferroptosis. CUT&Tag and RNA-seq identified SAT2 as a KAT2A target, and we confirmed that KAT2A-mediated H3K79succ enhances SAT2 expression, promoting Ferroptosis in DN.

Conclusion: This study uncovers the role of KAT2A in DN, demonstrating its promotion of inflammation and Ferroptosis through H3K79succ and SAT2 upregulation, offering insights into DN pathogenesis and potential therapeutic strategies.

Keywords
Diabetic nephropathy; Ferroptosis; H3K79 Succinylation; KAT2A; SAT2.
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