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
  • 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. [email protected].
  • 6. State Key Laboratory of Organ Failure Research, Guangzhou, China. [email protected].
  • 7. National Clinical Research Center of Kidney Disease, Guangzhou, China. [email protected].
  • 8. Guangdong Provincial Key Laboratory of Renal Failure Research, Guangzhou, China. [email protected].
  • 9. Biobank of Peking University First Hospital, Peking University First Hospital, Peking University, Beijing, China. [email protected].
  • # 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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