2. Academic Validation
  3. Renal tubular GSDME protects cisplatin nephrotoxicity by impeding OGT-STAT3-S100A7A axis in male mice

Renal tubular GSDME protects cisplatin nephrotoxicity by impeding OGT-STAT3-S100A7A axis in male mice

  • Nat Commun. 2025 Jul 24;16(1):6807. doi: 10.1038/s41467-025-62071-8.
Qingzhou Chen # 1 2 3 4,  Pengxiao Sun # 1 2 3 4,  Jiaxin Zhou 1 2 3 4,  Tantan Long 1 2 3 4,  An Xiao 1 2 3 4,  Zhuoliang Liu 1 2 3 4,  Shihui Xu 1 2 3 4,  Wenjing Lei 1 2 3 4,  Rui Zhang 1 2 3 4,  Jianwei Tian 1 2 3 4,  Miaomiao Zhou 1 2 3 4,  Zheng Hu 1 2 3 4,  Fengxin Zhu 1 2 3 4,  Jing Nie 5 6 7 8 9
Affiliations

Affiliations

  • 1 Division of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, China.
  • 2 State Key Laboratory of Organ Failure Research, Guangzhou, China.
  • 3 National Clinical Research Center of Kidney Disease, Guangzhou, China.
  • 4 Guangdong Provincial Key Laboratory of Renal Failure Research, Guangzhou, China.
  • 5 Division of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, China. niejing@smu.edu.cn.
  • 6 State Key Laboratory of Organ Failure Research, Guangzhou, China. niejing@smu.edu.cn.
  • 7 National Clinical Research Center of Kidney Disease, Guangzhou, China. niejing@smu.edu.cn.
  • 8 Guangdong Provincial Key Laboratory of Renal Failure Research, Guangzhou, China. niejing@smu.edu.cn.
  • 9 Biobank of Peking University First Hospital, Peking University First Hospital, Peking University, Beijing, China. niejing@smu.edu.cn.
  • # Contributed equally.
PMID: 40707439 DOI: 10.1038/s41467-025-62071-8
Abstract

Gasdermin E (GSDME) is known as a key executive protein of pro-inflammatory Pyroptosis. However, the function diversity of GSDME needs further investigation. Here, we show that GSDME expression is downregulated in kidney tissues after cisplatin treatment without detectable N-terminal fragment. Global and tubule-specific Gsdme deficiency aggravates cisplatin-induced renal injury. Mechanistically, loss of GSDME in proximal tubular cells facilitates the recruitment of OGT to the CUL4B-DDB1-WDR26 E3 ubiquitin Ligase complex, promoting OGT degradation and subsequently reducing STAT3 O-GlcNAcylation. This post-translational shift enhances STAT3 phosphorylation and induces upregulation of its downstream target gene, S100a7a. Elevated S100A7A promotes macrophage infiltration via RAGE activation, amplifying renal inflammation. Tubule-specific depleting S100a7a improves renal function and reduces renal injury and inflammation. These findings uncover a protective, non-pyroptotic function of GSDME in modulating O-GlcNAcylation and STAT3-S100A7A-RAGE signaling to maintain renal homeostasis under cisplatin stress in male mice.

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