摘要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 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.