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Liposomal UHRF1 siRNA shows lung fibrosis treatment potential through regulation of fibroblast activation
Demin Cheng, … , Yi Liu, Chunhui Ni
Demin Cheng, … , Yi Liu, Chunhui Ni
Published September 27, 2022
Citation Information: JCI Insight. 2022;7(22):e162831. https://doi.org/10.1172/jci.insight.162831.
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Research Article Pulmonology

Liposomal UHRF1 siRNA shows lung fibrosis treatment potential through regulation of fibroblast activation

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Abstract

Pulmonary fibrosis is a chronic and progressive interstitial lung disease associated with the decay of pulmonary function, which leads to a fatal outcome. As an essential epigenetic regulator of DNA methylation, the involvement of ubiquitin-like containing PHD and RING finger domains 1 (UHRF1) in fibroblast activation remains largely undefined in pulmonary fibrosis. In the present study, we found that TGF-β1–mediated upregulation of UHRF1 repressed beclin 1 via methylated induction of its promoter, which finally resulted in fibroblast activation and lung fibrosis both in vitro and in vivo. Moreover, knockdown of UHRF1 significantly arrested fibroblast proliferation and reactivated beclin 1 in lung fibroblasts. Thus, intravenous administration of UHRF1 siRNA–loaded liposomes significantly protected mice against experimental pulmonary fibrosis. Accordingly, our data suggest that UHRF1 might be a novel potential therapeutic target in the pathogenesis of pulmonary fibrosis.

Authors

Demin Cheng, Yue Wang, Ziwei Li, Haojie Xiong, Wenqing Sun, Sichuan Xi, Siyun Zhou, Yi Liu, Chunhui Ni

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Figure 3

The YAP/TEAD pathway contributes to the expression of UHRF1 in fibroblast activation.

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The YAP/TEAD pathway contributes to the expression of UHRF1 in fibroblas...
(A) The potential binding sites (including TEAD1 and TEAD4) at the UHRF1 promoter region by using the JASPAR database. (B) Target siRNA transfection significantly decreased the expression of TEAD1, TEAD4, and YAP in MRC-5 cells. Data are shown as the mean ± SEM (n = 3 in each group). (C) qRT-PCR detection of UHRF1 expression in MRC-5 cells after transfection with TEAD1, TEAD4, and YAP siRNA. Data are shown as the mean ± SEM (n = 3 in each group). (D–G) Western blot and corresponding densitometry analysis of TEAD1, TEAD4, YAP, and UHRF1 in MRC-5 cells and PLFs transfected with TEAD1, TEAD4, and YAP siRNA and their negative control (NC) siRNA and then treated with 5 ng/mL TGF-β1 for 48 hours. Data are shown as the mean ± SEM (n = 3 in each group). (H) Chromatin was harvested for immunoprecipitation with IgG, an anti-TEAD1 antibody, an anti-TEAD4 antibody, an anti-YAP antibody, and an anti–histone H3 antibody. The expression of UHRF1 was detected by qRT-PCR analysis. Data are shown as the mean ± SEM (n = 3 in each group). P values were from (B) a 2-tailed unpaired Student’s t test and (C and E–H) a 1-way ANOVA post hoc test with Tukey’s correction.

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