Renal tubular GSDME protects cisplatin nephrotoxicity by impeding OGT-STAT3-S100A7A axis in male mice
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 fragme...
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| Format: | Article |
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Nature Portfolio
2025-07-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-62071-8 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Qingzhou Chen |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-859e01a64e4b4ca88cc7025e4841b8c9 |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-859e01a64e4b4ca88cc7025e4841b8c92025-08-20T04:02:55ZengNature PortfolioNature Communications2041-17232025-07-0116112110.1038/s41467-025-62071-8Renal tubular GSDME protects cisplatin nephrotoxicity by impeding OGT-STAT3-S100A7A axis in male miceQingzhou Chen0Pengxiao Sun1Jiaxin Zhou2Tantan Long3An Xiao4Zhuoliang Liu5Shihui Xu6Wenjing Lei7Rui Zhang8Jianwei Tian9Miaomiao Zhou10Zheng Hu11Fengxin Zhu12Jing Nie13Division of Nephrology, Nanfang Hospital, Southern Medical UniversityDivision of Nephrology, Nanfang Hospital, Southern Medical UniversityDivision of Nephrology, Nanfang Hospital, Southern Medical UniversityDivision of Nephrology, Nanfang Hospital, Southern Medical UniversityDivision of Nephrology, Nanfang Hospital, Southern Medical UniversityDivision of Nephrology, Nanfang Hospital, Southern Medical UniversityDivision of Nephrology, Nanfang Hospital, Southern Medical UniversityDivision of Nephrology, Nanfang Hospital, Southern Medical UniversityDivision of Nephrology, Nanfang Hospital, Southern Medical UniversityDivision of Nephrology, Nanfang Hospital, Southern Medical UniversityDivision of Nephrology, Nanfang Hospital, Southern Medical UniversityDivision of Nephrology, Nanfang Hospital, Southern Medical UniversityDivision of Nephrology, Nanfang Hospital, Southern Medical UniversityDivision of Nephrology, Nanfang Hospital, Southern Medical UniversityAbstract 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.https://doi.org/10.1038/s41467-025-62071-8 |
| spellingShingle | 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 Renal tubular GSDME protects cisplatin nephrotoxicity by impeding OGT-STAT3-S100A7A axis in male mice Nature Communications |
| title | Renal tubular GSDME protects cisplatin nephrotoxicity by impeding OGT-STAT3-S100A7A axis in male mice |
| title_full | Renal tubular GSDME protects cisplatin nephrotoxicity by impeding OGT-STAT3-S100A7A axis in male mice |
| title_fullStr | Renal tubular GSDME protects cisplatin nephrotoxicity by impeding OGT-STAT3-S100A7A axis in male mice |
| title_full_unstemmed | Renal tubular GSDME protects cisplatin nephrotoxicity by impeding OGT-STAT3-S100A7A axis in male mice |
| title_short | Renal tubular GSDME protects cisplatin nephrotoxicity by impeding OGT-STAT3-S100A7A axis in male mice |
| title_sort | renal tubular gsdme protects cisplatin nephrotoxicity by impeding ogt stat3 s100a7a axis in male mice |
| url | https://doi.org/10.1038/s41467-025-62071-8 |
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