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

Qingzhou Chen, Pengxiao Sun, Jiaxin Zhou, Tantan Long, An Xiao, Zhuoliang Liu, Shihui Xu, Wenjing Lei, Rui Zhang, Jianwei Tian, Miaomiao Zhou, Zheng Hu, Fengxin Zhu and Jing Nie ()
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Qingzhou Chen: Southern Medical University
Pengxiao Sun: Southern Medical University
Jiaxin Zhou: Southern Medical University
Tantan Long: Southern Medical University
An Xiao: Southern Medical University
Zhuoliang Liu: Southern Medical University
Shihui Xu: Southern Medical University
Wenjing Lei: Southern Medical University
Rui Zhang: Southern Medical University
Jianwei Tian: Southern Medical University
Miaomiao Zhou: Southern Medical University
Zheng Hu: Southern Medical University
Fengxin Zhu: Southern Medical University
Jing Nie: Southern Medical University

Nature Communications, 2025, vol. 16, issue 1, 1-21

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-62071-8

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