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 pul-monary 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 expres-sion 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 LnicDACH1 might be a potential therapeutic target for pulmonary fibrosis.

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;Northern Translational Medicine Research and Cooperation Center,Heilongjiang Academy of Medical Sciences,Harbin Medical University,Harbin 150081,China;Zhuhai People's Hospital,Guangdong Provincial Key Laboratory of Tumor Interventional Diagnosis and Treatment,Zhuhai Hospital Affiliated with Jinan University,Jinan University,Zhuhai 519000,China;Department of Thoracic Surgery,Shanghai Pulmonary Hospital,Tongji University,Shanghai 200433,China;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;Research Unit of Noninfectious Chronic Diseases in Frigid Zone(2019RU070),Chinese Academy of Medical Sciences,Harbin 150081,China

[1]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-.LncRNA DACH1 protects against pulmonary fibrosis by binding to SRSF1 to suppress CTNNB1 accumulation)[J].药学学报（英文版）,2022(09):3602-3617

dachshund,LncDACH1,LnicDACH1

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