PU.1 aggravates hepatic sinusoidal obstruction syndrome by upregulating PTBP1 and activating the Wnt/β-catenin pathway

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Yang-41-305-318-2026.pdf(8.18 MB)
Date
2026
Authors
Yang, Li
Ju, Honglin
Chen, Zhiyuan
Cheng, Siqi
Liu, Ya
Wang, Xiangyang
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Abstract
Objective. Hepatic sinusoidal obstruction syndrome (HSOS) is a disease characterized by damage to hepatic sinusoidal endothelial cells (HSECs). This research investigates the role and regulatory pathway of PU box-binding protein (PU.1) in the progression of HSOS. Methods. We established an in vivo HSOS model through peritoneal administration of monocrotaline (MCT). Primary murine HSECs were isolated and treated with various concentrations of MCT to establish an in vitro HSOS model. PU.1 knockdown was achieved using lentiviral shRNA constructs, and its impact on oxidative stress, PTBP1 expression, β-catenin mRNA stability, and Wnt/β-catenin signaling was evaluated through kits, RT-qPCR, and western blot. Dual-luciferase and chromatin immunoprecipitation assays were conducted to assess the interaction between PU.1 and the PTBP1 promoter. The molecular association between PTBP1 and β-catenin mRNA was confirmed through RNA pull-down and RIP assays. Results. PU.1 was upregulated in MCT-induced HSOS, contributing to elevated oxidative stress and activation of the Wnt/β-catenin pathway. PU.1 directly enhanced PTBP1 transcription, which stabilized β-catenin mRNA and sustained Wnt/β-catenin signaling. PU.1 knockdown alleviated oxidative stress, reduced liver damage, and disrupted the PTBP1-β-catenin interaction, leading to Wnt/β-catenin activity inhibition. Overexpression of PTBP1 reversed the protective effects of PU.1 knockdown, reinstating oxidative stress and reactivating Wnt/β-catenin signaling. Conclusion. PU.1 facilitated HSOS pathogenesis by promoting the transcriptional activity of PTBP1 and activating the Wnt/β-catenin pathway. Targeting PU.1 can serve as a promising therapeutic strategy for reducing oxidative stress and liver damage in HSOS.
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Hepatic sinusoidal obstruction syndrome , PU.1 , PTBP1 , β-catenin , Oxidative stress
Citation
Histology and Histopathology, vol.41, nº2(2026)305-318
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http://hdl.handle.net/10201/184449
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Histology and histopathology, Vol.41, Nº2, (2026)
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