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<p>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 <i>Gsdme</i> 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, <i>S100a7a</i>. Elevated S100A7A promotes macrophage infiltration via RAGE activation, amplifying renal inflammation. Tubule-specific depleting <i>S100a7a</i> 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.</p>

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

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年7月24日

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  • 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,
  • Jing Nie

摘要

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.