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Bosutinib alleviates peritoneal fibrosis by regulating mesothelial-to-mesenchymal transition through inhibition of the PI3K/AKT pathway

Year: 2025

Type: article

Abstract: Peritoneal dialysis (PD) is a critical renal replacement therapy for patients with end-stage renal disease (ESRD). However, long-term PD is associated with progressive peritoneal membrane damage, mesothelial-to-mesenchymal transition (MMT), angiogenesis, and vasculopathy; these conditions ultimately result in ultrafiltration failure and the cessation of PD. Currently, effective clinical treatments for peritoneal fibrosis are limited. In our study, we screened an Food and Drug Administration（FDA）-approved drug library to identify compounds capable of reversing the inhibition of HMrSV5 cell viability under high-glucose conditions. Through this screening, we identified ten drugs that could reverse the inhibition of HMrSV5 cell viability under high-glucose conditions, five of which demonstrated a dose-dependent effect on cell viability. Among these drugs, bosutinib was identified as the optimal drug. Western blot analysis revealed that bosutinib effectively attenuated MMT in mesothelial cells under high-glucose conditions, as evidenced by the upregulation of E-cadherin and the downregulation of α-SMA and TGF-β. Furthermore, in a mouse model in which daily administration of dialysis fluid induced peritoneal fibrosis, bosutinib treatment reduced the expression of α-SMA, TGF-β and fibronectin. Early treatment with bosutinib prevented PD-related Peritoneal fibrosis(PF)in a mouse model. Our findings suggest that bosutinib may improve peritoneal fibrosis by inhibiting MMT. After transcriptomic analysis of the effects of bosutinib for the treatment of PF, the assessment of relevant genes and pathways revealed a significant enrichment in the PI3K/AKT signalling pathway, which was confirmed by our western blotting results showing that bosutinib ameliorated peritoneal fibrosis by inhibiting the PI3K/AKT signalling pathway. Thus, our study demonstrated that bosutinib alleviates peritoneal fibrosis by regulating mesothelial-to-mesenchymal transition through the inhibition of the PI3K/AKT pathway.

Source: Biochemical Pharmacology

DOI: 10.1016/j.bcp.2025.117412