1. Academic Validation
  2. Ligustilide attenuates airway remodeling in COPD mice by covalently binding to MH2 domain of Smad3 in pulmonary epithelium, disrupting the Smad3-SARA interaction

Ligustilide attenuates airway remodeling in COPD mice by covalently binding to MH2 domain of Smad3 in pulmonary epithelium, disrupting the Smad3-SARA interaction

  • Phytother Res. 2022 Oct 10. doi: 10.1002/ptr.7655.
Yu-Jie Lu 1 Lin Niu 2 Fu-Kui Shen 1 Wen Yang 1 Yang Xie 3 Su-Yun Li 3 4 Min Jiang 1 Gang Bai 1
Affiliations

Affiliations

  • 1 State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin, People's Republic of China.
  • 2 Laboratory of Compound Drugs and Systems Biology, Tianjin University of Traditional Chinese Medicine, Tianjin, People's Republic of China.
  • 3 Department of Respiratory Diseases, The Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou, People's Republic of China.
  • 4 Collaborative Innovation Center for Chinese Medicine and Respiratory Diseases co-constructed by Henan province & Education Ministry of P.R., China, Henan University of Chinese Medicine, Zhengzhou, People's Republic of China.
Abstract

Airway remodeling is one of the hallmarks of chronic obstructive pulmonary disease (COPD) and is closely related to the dysregulation of epithelial-mesenchymal transition (EMT). SMAD3, an important transcriptional regulator responsible for transducing TGF-β1 signals, is a promising target for EMT modulation. We found that ligustilide (Lig), a novel SMAD3 covalent inhibitor, effectively inhibited airway remodeling in cigarette smoke (CS) combined with lipopolysaccharide (LPS)-induced COPD mice. Oral administration of an alkynyl-modified Lig probe was used to capture and trace target proteins in mouse lung tissue, revealing SMAD3 in airway epithelium as a key target of Lig. Protein mass spectrometry and SMAD3 mutation analysis via in-gel imaging indicated that the epoxidized metabolite of Lig covalently binds to the MH2 domain of SMAD3 at Cys331/337. This irreversible bonding destroys the interaction of Smad3-SARA, prevents SMAD3 phosphorylation activation, and subsequently suppresses the nuclear transfer of p-Smad3, the EMT process, and collagen deposition in TGF-β1-stimulated BEAS-2B cells and COPD mice. These findings provide experimental support that Lig attenuates COPD by repressing airway remodeling which is attributed to its suppression on the activation of EMT process in the airway epithelium via targeting SMAD3 and inhibiting the recruitment of the Smad3-SARA heterodimer in the TGF-β1/SMAD3 pathway.

Keywords

Smad3; airway remodeling; covalently binding; epithelial-mesenchymal transition; ligustilide.

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