Tetrandrine modulates SQSTM1-mediated selective autophagy and protects
pulmonary fibrosis
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.