This study reveals the molecular mechanism by which β-catenin activates mitochondrial fission protein Drp1, subsequently inducing mesothelial cell senescence and promoting peritoneal fibrosis. Additionally, the use of senolytic drugs, D + Q, effectively alleviates peritoneal fibrosis, suggesting that targeting cell senescence and β-catenin signaling may represent a novel therapeutic strategy.
Literature Overview
In this paper, 'β-catenin initiates peritoneal fibrosis by triggering mitochondrial fission-mediated mesothelial cell senescence fate transition', published in the journal 'Military Medical Research', the authors reviewed and summarized the pathogenesis of peritoneal fibrosis, particularly focusing on mesothelial cell senescence fate transition under long-term peritoneal dialysis. The study highlights the β-catenin signaling pathway, finding that it promotes mitochondrial fission by upregulating Drp1 expression, thereby inducing cell senescence and SASP factor (e.g., TGF-β1) secretion, ultimately activating fibroblasts and leading to peritoneal fibrosis. Moreover, Drp1 and TGF-β1 levels in clinical samples positively correlate with dialysis duration, and β-catenin knockout or KYA1797K treatment effectively alleviates fibrosis, suggesting this signaling axis as a potential therapeutic target.
Background Knowledge
Peritoneal dialysis (PD) is a vital alternative therapy for end-stage renal disease; however, prolonged exposure to high-glucose dialysate leads to peritoneal fibrosis, compromising dialysis efficacy and triggering encapsulating peritoneal sclerosis. As the first line of defense in the peritoneum, mesothelial cells are prone to pathological changes such as senescence, apoptosis, and mesothelial-mesenchymal transition (MMT) under long-term PD conditions. Cellular senescence is accompanied by SASP factor secretion, which can activate fibroblasts and promote extracellular matrix (ECM) deposition. β-catenin, a key transcription factor in the Wnt signaling pathway, has been reported to promote senescence and fibrosis in renal tubular epithelial cells. However, its role and mechanisms in peritoneal mesothelial cells remain unclear. Moreover, mitochondrial fission, mediated by Drp1, has been linked to cellular metabolic dysfunction and senescence. This study further elucidates the critical role of the β-catenin-Drp1-TGFβ1 signaling axis in peritoneal fibrosis and validates its potential as a therapeutic target, providing a theoretical basis for developing anti-fibrosis interventions.
Research Methods and Experiments
The research team employed single-cell RNA sequencing (scRNA-seq) to analyze the senescence fate trajectory of peritoneal mesothelial cells in long-term PD patients, combined with peritoneal biopsies and dialysate samples to validate senescence-related markers. For mouse models, they established a mesothelial cell-specific β-catenin knockout model using AAV1-Cre infection and conducted intervention experiments using KYA1797K (a β-catenin inhibitor) and D + Q (a senolytic drug). Furthermore, human peritoneal mesothelial cell lines (HMrSV5) were cultured in vitro and subjected to gene overexpression, knockdown, and ChIP assays to explore the regulatory mechanism of β-catenin on Drp1.
Key Conclusions and Perspectives
Research Significance and Prospects
This study systematically clarifies the central role of β-catenin in mesothelial cell senescence and elucidates its molecular connection with mitochondrial fission, SASP secretion, and fibroblast activation. Targeting β-catenin or senescent cells may represent a promising strategy for delaying peritoneal fibrosis. Future studies should investigate the conservation of this signaling axis in other fibrotic diseases and evaluate the clinical application potential of senolytic drugs.
Conclusion
Peritoneal fibrosis is a major clinical complication in long-term peritoneal dialysis patients, involving mesothelial cell senescence, mitochondrial fission dysregulation, and fibroblast activation. This study, through multi-omics analysis, animal models, and in vitro experiments, defines the central role of the β-catenin-Drp1-TGFβ1 signaling axis in mesothelial cell senescence and peritoneal fibrosis. Furthermore, it demonstrates that β-catenin inhibition via KYA1797K or senescent cell clearance by D + Q effectively mitigates fibrosis phenotypes. These findings provide novel therapeutic targets and intervention strategies for peritoneal fibrosis and suggest a broad clinical potential for senolytic therapies in fibrotic diseases.
