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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 1

UHRF1 is overexpressed in TGF-β1–stimulated fibroblasts and fibrotic lungs.

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UHRF1 is overexpressed in TGF-β1–stimulated fibroblasts and fibrotic lun...
(A–C) Western blot and corresponding densitometry analysis of fibronectin, collagen I, α-SMA, and UHRF1 in TGF-β1–treated (0, 1, 2, 5 ng/mL for 48 hours) MRC-5 cells and PLFs. Data are shown as the mean ± SEM (n = 3 in each group). (D) Immunofluorescence staining of UHRF1 in MRC-5 cells. Red represents UHRF1; blue represents nuclear DNA staining by DAPI. (E) Immunofluorescence staining of UHRF1 in mouse lung tissues. Red represents UHRF1; blue represents DAPI. (F) Representative results of H&E and UHRF1 IHC staining in lung sections from patients with silicosis and idiopathic pulmonary fibrosis (IPF) and normal participants. (G and H) Western blot and densitometric analysis of fibronectin, collagen I, α-SMA, and UHRF1 protein in saline- or silica-treated mouse lung tissues. Data are shown as the mean ± SEM (n = 3 in each group). Scale bar: 25 μm (D); 100 μm (E and F). P values were from (B and C) a 1-way ANOVA post hoc test with Tukey’s correction or (H) 2-tailed unpaired Student’s t test.

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