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Tetrandrine modulates SQSTM1-mediated selective autophagy and protects pulmonary fibrosis
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  • Yuanyuan Liu,
  • Wenshan Zhong,
  • Jinming Zhang,
  • Weimou Chen,
  • Ye Lu,
  • Yujie Qiao,
  • Zhaojin Zeng,
  • Haohua Huang,
  • Fei Zou,
  • Xiaojing Meng,
  • shaoxi cai,
  • Hangming Dong
Yuanyuan Liu
Southern Medical University Nanfang Hospital
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Wenshan Zhong
Southern Medical University Nanfang Hospital
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Jinming Zhang
Southern Medical University Nanfang Hospital
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Weimou Chen
Southern Medical University Nanfang Hospital
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Ye Lu
Southern Medical University Nanfang Hospital
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Yujie Qiao
Southern Medical University Nanfang Hospital
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Zhaojin Zeng
Southern Medical University Nanfang Hospital
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Haohua Huang
Southern Medical University Nanfang Hospital
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Fei Zou
Southern Medical University
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Xiaojing Meng
Southern Medical University
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shaoxi cai
Southern Medical University Nanfang Hospital
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Hangming Dong
Southern Medical University Nanfang Hospital
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Abstract

Background and Purpose Idiopathic pulmonary fibrosis is a progressive fatal disease characterized by interstitial remodeling, with high lethality and a lack of effective medical therapies. Tetrandrine has been proposed to present anti-fibrotic effects, but the efficacy and mechanisms of tetrandrine against lung fibrosis has not been systematically evaluated. We sought to study the potential therapeutic effects and mechanisms of tetrandrine in lung fibrosis. Experimental Approach The anti-fibrotic effects of tetrandrine were evaluated in bleomycin-induced mouse models and TGF-β1-stimulated murine lung fibroblasts. We performed Chromatin Immunoprecipitation (ChIP), Immunoprecipitation (IP) and mRFP-GFP-MAP1LC3B adenovirus construct to investigate the novel mechanisms of tetrandrine-induced autophagy. Key Results Tetrandrine decreased TGF-β1-induced expression of α-smooth muscle actin, fibronectin, vimentin and type 1 collagen and proliferation in fibroblasts. Tetrandrine restored TGF-β1-induced impaired autophagy, accompanied by the up-regulation and enhanced interaction of SQSTM1 and MAP1LC3-Ⅱ. ChIP studies revealed that NRF2 bound to SQSTM1 promoter in tetrandrine-induced autophagy. Furthermore, TGF-β1-induced phosphorylated mTOR was inhibited by tetrandrine, with reduced activation levels of Rheb. In vivo tetrandrine suppressed the bleomycin-induced expression of fibrotic markers and improved pulmonary function. Conclusion and Implications Our data suggest that tetrandrine might be recognized as a novel autophagy inducer, thus attenuating lung fibrosis. Tetrandrine should be investigated as a novel therapeutic strategy for IPF.