Demethyleneberberine Alleviates Pulmonary Fibrosis through Disruption of USP11 Deubiquitinating GREM1

作者：Chuang Ge, Mengsheng Huang, Yanhong Han, Chang Shou, Dongyin Li, Yubin Zhang · 发表于：Pharmaceuticals · 年份：2024 · DOI：10.3390/ph17030279 · 被引用次数：12 · 研究领域：Interstitial Lung Diseases and Idiopathic Pulmonary Fibrosis、Chronic Obstructive Pulmonary Disease (COPD) Research、Cystic Fibrosis Research Advances

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a fatal and chronic interstitial lung disease. Intricate pathogenesis of pulmonary fibrosis and only two approved medications with side effects and high cost bring us the challenge of fully understanding this lethal disease and urgency to find more safe and low-cost therapeutic alternatives. PURPOSE: Demethyleneberberine (DMB) has been demonstrated to have various anti-inflammatory, antioxidant, antifibrosis and anti-cancer bioactivities. The objective of this study was to evaluate the effect of DMB on pulmonary fibrosis and investigate the mechanism. METHODS: Bleomycin (BLM)-induced pulmonary fibrosis was established in mice to evaluate the antifibrotic effect of DMB in vivo. A549 and MRC5 cells were used to evaluate the effect of DMB on epithelial-mesenchymal transition (EMT) and fibroblast-myofibroblast transition (FMT) in vitro. High throughput sequencing, biotin-avidin system and site-directed mutagenesis were applied to explore the mechanism of DMB in alleviating pulmonary fibrosis. RESULTS: DMB alleviated BLM-induced pulmonary fibrosis in vivo by improving the survival state of mice, significantly reducing pulmonary collagen deposition and oxidative stress and improving lung tissue morphology. Meanwhile, DMB was demonstrated to inhibit epithelial-mesenchymal transition (EMT) and fibroblast-myofibroblast transition (FMT) in vitro. High throughput sequencing analysis indicated that GREM1, a highly upregulated profibrotic...