Targeting Stat3 with conditional knockout or PROTAC technology alleviates renal injury by Limiting pyroptosis

作者：Ming-Lu Ji, Jianan Wang, Mingfei Wu, Chuan‐hui Xu, Mengmeng Zhang, Wen-bao Chang, Xin-fei Mao, Chao Li, Ju-tao Yu, Danfeng Zhang, Xiao-Guo Suo, Shaoxi Diao, Nannan Ma, Ying Chen, Rui Hou, Lu Hao, Shuai-shuai Xie, Yuhang Dong, Qi Zhu, Xin Chen, Tao Xu, Wei Shao, Juan Jin, Jiagen Wen, Xiaowu Dong, Wenbin Wang, Jinxin Che, Xiao‐Ming Meng · 发表于：EBioMedicine · 年份：2025 · DOI：10.1016/j.ebiom.2025.105739 · 被引用次数：15 · 研究领域：Cytokine Signaling Pathways and Interactions、Acute Kidney Injury Research、Cancer Mechanisms and Therapy

BACKGROUND: Acute kidney injury (AKI) is a critical clinical syndrome with high morbidity, mortality, and no effective treatment in clinical practice. The role of the Signal Transducer and Activator of Transcription 3 (Stat3) in AKI remains controversial, and its complex regulatory mechanisms must be further explored. METHODS: We generated renal tubular epithelial cells Stat3 conditional knockout (cKO) mice and used them in cecal ligation and puncture (CLP) and ischaemia-reperfusion (I/R) induced AKI models. Additionally, proteolysis-targeting chimaera (PROTAC) compound E034 was designed and synthesised. We also utilised human kidney tissues, mouse renal tubular epithelial cells (mTECs) and HK-2 cells for further studies, including immunohistochemistry, Western blot analysis, Real-time PCR, chromatin immunoprecipitation (ChIP) and RNA sequencing, scanning electron microscopy (SEM) and Co-Immunoprecipitation (Co-IP) assay. FINDINGS: An upregulation of total Stat3 protein was observed in AKI mouse models, which correlated with patient biopsy results. This increase may be attributed to histone H3K27 acetylation. Stat3 knockout in renal tubular epithelial cells significantly reduced AKI injury and inflammation in mice. Mechanistically, Stat3 induces the transcription of tripartite motif-containing protein 21 (Trim21), triggering a cascade that activates gasdermin D (Gsdmd), resulting in pyroptosis. Administration of E034, which selectively targets Stat3 for ubiquitination and deg...