Chen Qingzhou, Sun Pengxiao, Zhou Jiaxin, Long Tantan, Xiao An, Liu Zhuoliang, Xu Shihui, Lei Wenjing, Zhang Rui, Tian Jianwei, Zhou Miaomiao, Hu Zheng, Zhu Fengxin, Nie Jing
Division of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, China.
State Key Laboratory of Organ Failure Research, Guangzhou, China.
Nat Commun. 2025 Jul 24;16(1):6807. doi: 10.1038/s41467-025-62071-8.
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.
Gasdermin E（GSDME）是促炎性细胞焦亡的关键执行蛋白。然而，GSDME的功能多样性仍需进一步研究。在此，我们发现顺铂处理后肾组织中GSDME表达下调，且未检测到N端片段。全身和肾小管特异性Gsdme缺陷会加重顺铂诱导的肾损伤。机制上，近端肾小管细胞中GSDME的缺失促进了OGT募集到CUL4B-DDB1-WDR26 E3泛素连接酶复合物，促进OGT降解，随后减少STAT3 O-GlcNAc糖基化。这种翻译后变化增强了STAT3磷酸化并诱导其下游靶基因S100a7a上调。升高的S100A7A通过RAGE激活促进巨噬细胞浸润，放大肾脏炎症。肾小管特异性敲低S100a7a可改善肾功能并减轻肾损伤和炎症。这些发现揭示了GSDME在调节O-GlcNAc糖基化和STAT3-S100A7A-RAGE信号传导以维持雄性小鼠顺铂应激下肾脏稳态中的保护性非细胞焦亡功能。
