LncRNA <i>DACH1</i> protects against pulmonary fibrosis by binding to SRSF1 to suppress <i>CTNNB1</i> accumulation.

Jian Sun; Tongzhu Jin; Zhihui Niu; Jiayu Guo; Yingying Guo; Ruoxuan Yang; Qianqian Wang; Huiying Gao; Yuhan Zhang; Tianyu LI; Wenxin HE; Zhixin LI; Wenchao MA; Wei SU; Liangliang LI; Xingxing Fan; Hongli Shan; Haihai Liang

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LncRNA DACH1 protects against pulmonary fibrosis by binding to SRSF1 to suppress CTNNB1 accumulation.

Author: Jian SUN ¹ ; Tongzhu JIN ¹ ; Zhihui NIU ¹ ; Jiayu GUO ¹ ; Yingying GUO ¹ ; Ruoxuan YANG ¹ ; Qianqian WANG ¹ ; Huiying GAO ¹ ; Yuhan ZHANG ¹ ; Tianyu LI ¹ ; Wenxin HE ² ; Zhixin LI ² ; Wenchao MA ¹ ; Wei SU ¹ ; Liangliang LI ¹ ; Xingxing FAN ³ ; Hongli SHAN ¹ ; Haihai LIANG ¹
Author Information

1. Department of Pharmacology (State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin 150081, China.
2. Department of Thoracic Surgery, Shanghai Pulmonary Hospital, Tongji University, Shanghai 200433, China.
3. State Key Laboratory of Quality Research in Chinese Medicine/Macau Institute for Applied Research in Medicine and Health, Macau University of Science and Technology, Macau (SAR), China.
Publication Type:Journal Article
Keywords: CTNNB1; Extracellular matrix; Fibroblast; Idiopathic pulmonary fibrosis; LncRNA DACH1; Myofibroblast; Proliferation; SRSF1
From: Acta Pharmaceutica Sinica B 2022;12(9):3602-3617
CountryChina
Language:English
Abstract: Idiopathic pulmonary fibrosis (IPF) is a progressive disease with unknown etiology and limited therapeutic options. Activation of fibroblasts is a prominent feature of pulmonary fibrosis. Here we report that lncRNA DACH1 (dachshund homolog 1) is downregulated in the lungs of IPF patients and in an experimental mouse model of lung fibrosis. LncDACH1 knockout mice develop spontaneous pulmonary fibrosis, whereas overexpression of LncDACH1 attenuated TGF-β1-induced aberrant activation, collagen deposition and differentiation of mouse lung fibroblasts. Similarly, forced expression of LncDACH1 not only prevented bleomycin (BLM)-induced lung fibrosis, but also reversed established lung fibrosis in a BLM model. Mechanistically, LncDACH1 binding to the serine/arginine-rich splicing factor 1 (SRSF1) protein decreases its activity and inhibits the accumulation of Ctnnb1. Enhanced expression of SRSF1 blocked the anti-fibrotic effect of LncDACH1 in lung fibroblasts. Furthermore, loss of LncDACH1 promoted proliferation, differentiation, and extracellular matrix (ECM) deposition in mouse lung fibroblasts, whereas such effects were abolished by silencing of Ctnnb1. In addition, a conserved fragment of LncDACH1 alleviated hyperproliferation, ECM deposition and differentiation of MRC-5 cells driven by TGF-β1. Collectively, LncDACH1 inhibits lung fibrosis by interacting with SRSF1 to suppress CTNNB1 accumulation, suggesting that LncDACH1 might be a potential therapeutic target for pulmonary fibrosis.