β-catenin initiates peritoneal fibrosis by triggering mitochondrial fission-mediated mesothelial cell senescence fate transition

作者：Xiaoxu Wang, Weijie Zhong, Jie-Mei Li, Di Wang, Shuangqin Chen, Jinhua Miao, Weiwei Shen, Xiaolong Li, Jiewu Huang, Shan Zhou, Cheng Wang, Jun Ai, Lili Zhou · 发表于：Military Medical Research · 年份：2025 · DOI：10.1186/s40779-025-00669-1 · 被引用次数：3 · 研究领域：Intestinal and Peritoneal Adhesions、Dialysis and Renal Disease Management、Occupational and environmental lung diseases

BACKGROUND: Peritoneal fibrosis represents a major clinical challenge for end-stage renal disease (ESRD) patients when they are undergoing peritoneal dialysis (PD). Single-cell RNA sequencing identified that peritoneal mesothelial cells undergo a senescence fate transition in long-term PD patients. Whereas the existence of mesothelial cell senescence and the underlying mechanisms should be thoroughly explored. METHODS: To further investigate mesothelial cell senescence, we utilized a clinical cohort comprising dialysate effluents from PD patients and peritoneal biopsy specimens, peritoneal dialysis fluid (PDF)-induced mouse models, and cultured primary mesothelial cells. Single-cell RNA sequencing, transcriptome sequencing, immunofluorescence, Western blotting, and other analyses were administered. To validate the critical role of β-catenin in mesothelial cell senescence, β-catenin knockout mice were employed. Additionally, the senolytic drugs dasatinib plus quercetin were administered to PDF mice to assess the key role of mesothelial cell senescence in peritoneal fibrosis. RESULTS: Single-cell RNA sequencing demonstrated that mesothelial cells derived from long-term PD patients are major trend to senescence fate. Moreover, β-catenin signaling was significantly upregulated, as well as transforming growth factor-β (TGF-β) pathways. We observed that senescent mesothelial cells were highly increased in both dialysate effluent and peritoneal biopsies of long-term PD patients. In ...