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

Xiao-Xu Wang; Wei-Jie Zhong; Jie-Mei Li; Di Wang; Shuang-Qin Chen; Jin-Hua Miao; Wei-Wei Shen; Xiao-Long Li; Jie-Wu Huang; Shan Zhou; Cheng Wang; Jun Ai; Li-Li Zhou

doi:10.1186/s40779-025-00669-1

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

RESEARCH | Updated：2026-08-20

- β-catenin initiates peritoneal fibrosis by triggering mitochondrial fission-mediated mesothelial cell senescence fate transition
- β-catenin initiates peritoneal fibrosis by triggering mitochondrial fission-mediated mesothelial cell senescence fate transition
- Military Medical Research 2026年13卷第6期页码：894-915
- Affiliations：
  
  Division of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
  State Key Laboratory of Multi-Organ Injury Prevention and Treatment, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
  National Clinical Research Center for Kidney Disease, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
  Guangdong Provincial Institute of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
  Guangdong Provincial Key Laboratory of Renal Failure Research, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
  Division of Nephrology, Department of Medicine, the Fifth Affiliated Hospital of Sun Yat-Sen University, Zhuhai 519000, Guangdong, China
- Author bio：
  
  * Cheng Wang wangch2@mail.sysu.edu.cn
  Jun Ai aij1980@smu.edu.cn
  Li-Li Zhou jinli730@smu.edu.cn
- Funds：
  
  the National Natural Science Foundation of China(82225010;82370744;82400881);the Guangdong Basic and Applied Basic Research Foundation(2023A1515110906);the Postdoctoral Science Foundation of China(2023M731558);the Postdoctoral Fellowship Program of China Postdoctoral Science Foundation(GZC20231060)
- DOI：10.1186/s40779-025-00669-1
  中图分类号：
- 收稿：2025-02-19，
  
  录用：2025-11-03，
  
  网络首发：2025-12-01，
  
  纸质出版：2026-06
- Accepted：
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Xiao-Xu Wang, Wei-Jie Zhong, Jie-Mei Li, 等. β-catenin initiates peritoneal fibrosis by triggering mitochondrial fission-mediated mesothelial cell senescence fate transition[J]. Military Medical Research, 2026,13(6):894-915.

Xiao-Xu Wang, Wei-Jie Zhong, Jie-Mei Li, et al. β-catenin initiates peritoneal fibrosis by triggering mitochondrial fission-mediated mesothelial cell senescence fate transition[J]. Military Medical Research, 2026, 13(6): 894-915.
Xiao-Xu Wang, Wei-Jie Zhong, Jie-Mei Li, 等. β-catenin initiates peritoneal fibrosis by triggering mitochondrial fission-mediated mesothelial cell senescence fate transition[J]. Military Medical Research, 2026,13(6):894-915. DOI： 10.1186/s40779-025-00669-1.

Xiao-Xu Wang, Wei-Jie Zhong, Jie-Mei Li, et al. β-catenin initiates peritoneal fibrosis by triggering mitochondrial fission-mediated mesothelial cell senescence fate transition[J]. Military Medical Research, 2026, 13(6): 894-915. DOI： 10.1186/s40779-025-00669-1.

摘要

Abstract

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 trans-forming 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 dialysate effluent

matrix metalloproteinase-7 (MMP-7)

an indicator of downstream targets of β-catenin

was positively correlated with TGF-β1. Both biomarkers were also positively associated with PD duration. Mechanistically

we found that β-catenin promotes dynamin-related protein 1 (Drp1) expression

a key mediator of mitochondrial fission

thereby inducing mesothelial cell senescence. Then

TGF-β1 was secreted to activate the Smad signaling pathway in fibroblasts

leading to myofibroblast activation and subsequent peritoneal fibrosis. Notably

administration of senolytic drugs

dasatinib plus quercetin

significantly alleviated peritoneal fibrosis regardless of treatment timing.

Conclusion

Targeting β-catenin signaling and mesothelial cell senescence may represent potential therapeutic interventions for preventing peritoneal fibrosis.

关键词

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references

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