Department of Occupational Medical and Environmental Health, Key Laboratory of Modern Toxicology, Ministry of Education, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, China.
Thoracic Epigenetics Section, Thoracic Surgery Branch, National Cancer Institute, NIH, Bethesda, Maryland, USA.
JCI Insight. 2022 Nov 22;7(22):e162831. doi: 10.1172/jci.insight.162831.
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.
肺纤维化是一种慢性进行性间质性肺疾病，与肺功能下降有关，可导致致命后果。泛素样含 PH 和环指域蛋白 1（UHRF1）作为 DNA 甲基化的重要表观遗传调节剂，其在肺纤维化中对成纤维细胞激活的作用在很大程度上尚不清楚。在本研究中，我们发现 TGF-β1 介导的 UHRF1 上调通过其启动子的甲基化诱导抑制了 beclin 1，最终导致体外和体内成纤维细胞的激活和肺纤维化。此外，敲低 UHRF1 可显著抑制肺成纤维细胞的增殖并重新激活 beclin 1。因此，静脉内给予负载 UHRF1 siRNA 的脂质体可显著保护小鼠免受实验性肺纤维化的影响。因此，我们的数据表明，UHRF1 可能是肺纤维化发病机制中的一个新的潜在治疗靶点。
