Journal
PHARMACOLOGICAL RESEARCH
Volume 174, Issue -, Pages -Publisher
ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD
DOI: 10.1016/j.phrs.2021.105923
Keywords
Idiopathic pulmonary fibrosis; Disulfiram; Fibroblast; TGF-beta/SMAD signalling; SMAD3
Categories
Funding
- National Natural Science Foundation of China [81973329, 82073858, 81773741, 82173821]
- Natural Science Foundation of Shanghai [21ZR1432700]
- Shanghai Jiao Tong University Scientific and Technological Innovation Funds [19X160010005]
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DSF inhibits pulmonary fibrosis by targeting TGF-beta/SMAD signaling pathway, making it a promising therapeutic candidate for idiopathic pulmonary fibrosis (IPF).
Idiopathic pulmonary fibrosis (IPF) induces significant morbidity and mortality, for which there are limited therapeutic options available. Here, we found that tetraethylthiuram disulphide (disulfiram, DSF), a derivative of thiuram, used in the treatment of alcohol abuse, has an inhibitory effect on bleomycin (BLM)-induced pulmonary fibrosis via the attenuation of the fibroblast-to-myofibroblast transition, migration, and proliferation of fibroblasts. Furthermore, DSF inhibited the activation of primary pulmonary fibroblasts and fibroblast cell line under transforming growth factor-beta 1 (TGF-beta 1) challenge. Mechanistically, the anti-fibrotic effect of DSF on fibroblasts depends on the inhibition of TGF-beta signalling. We further determined that DSF interrupts the interaction between SMAD3 and TGF-beta receptor I (TBR I), and identified that DSF directly binds with SMAD3, in which Trp326, Thr330, and Cys332 of SMAD3 are critical binding sites for DSF. Collectively, our results reveal a powerful anti-fibrotic function of DSF in pulmonary fibrosis through the inhibition of TGF-beta/SMAD signalling in pulmonary fibroblasts, indicating that DSF is a promising therapeutic candidate for IPF.
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