2. Academic Validation
  3. MPT0E028, a novel pan-HDAC inhibitor, prevents pulmonary fibrosis through inhibition of TGF-β-induced CTGF expression in human lung fibroblasts: Involvement of MKP-1 activation

MPT0E028, a novel pan-HDAC inhibitor, prevents pulmonary fibrosis through inhibition of TGF-β-induced CTGF expression in human lung fibroblasts: Involvement of MKP-1 activation

  • Eur J Pharmacol. 2024 Aug 15:977:176711. doi: 10.1016/j.ejphar.2024.176711.
Chia-Hao Liu 1,  Hong-Sheng Lee 2,  Jing-Ping Liou 3,  Hung-Sheng Hua 1,  Wun-Hao Cheng 4,  Fara Silvia Yuliani 5,  Bing-Chang Chen 6,  Chien-Huang Lin 7
Affiliations

Affiliations

  • 1 Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan.
  • 2 Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan; Chen Wei-Tien Research Center of Thoracic Medicine, Taipei Medical University, Taipei, Taiwan.
  • 3 School of Pharmacy, College of Pharmacy, Taipei Medical University, Taipei, Taiwan.
  • 4 School of Respiratory Therapy, College of Medicine, Taipei Medical University, Taipei, Taiwan; Respiratory Therapy, Division of Pulmonary Medicine, Department of Internal Medicine, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan.
  • 5 Department of Pharmacology and Therapy, Faculty of Medicine, Public Health and Nursing, Universitas Gadjah Mada, Yogyakarta, Indonesia.
  • 6 Chen Wei-Tien Research Center of Thoracic Medicine, Taipei Medical University, Taipei, Taiwan; School of Respiratory Therapy, College of Medicine, Taipei Medical University, Taipei, Taiwan; Respiratory Therapy, Division of Pulmonary Medicine, Department of Internal Medicine, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan. Electronic address: bcchen@tmu.edu.tw.
  • 7 Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan; Chen Wei-Tien Research Center of Thoracic Medicine, Taipei Medical University, Taipei, Taiwan. Electronic address: chlin@tmu.edu.tw.
PMID: 38839029 DOI: 10.1016/j.ejphar.2024.176711
Abstract

Histone deacetylase (HDAC) inhibitors are potential candidates for treating pulmonary fibrosis. MPT0E028, a novel pan-HDAC inhibitor, has been reported to exhibit antitumor activity in several Cancer cell lines. In this study, we investigated the mechanism underlying the inhibitory effects of MPT0E028 on the expression of fibrogenic proteins in human lung fibroblasts (WI-38). Our results revealed that MPT0E028 inhibited transforming growth factor-β (TGF-β)-, thrombin-, and endothelin 1-induced connective tissue growth factor (CTGF) expression in a concentration-dependent manner. In addition, MPT0E028 suppressed TGF-β-stimulated expression of fibronectin, Collagen I, and α-smooth muscle actin (α-SMA). Furthermore, MPT0E028 inhibited the TGF-β-induced phosphorylation of c-Jun N-terminal kinase (JNK), p38, and extracellular signal-regulated kinase (ERK). MPT0E028 reduced the increase in SMAD3 and c-Jun phosphorylation, and SMAD3-and activator protein-1 (AP-1)-luciferase activities under TGF-β stimulation. Transfection with mitogen-activated protein kinase phosphatase-1 (MKP-1) siRNA reversed the suppressive effects of MPT0E028 on TGF-β-induced increases in CTGF expression; JNK, p38, and ERK phosphorylation; and SMAD3 and AP-1 activation. Moreover, MPT0E028 increased MKP-1 acetylation and activity in WI-38 cells. Pretreatment with MPT0E028 reduced the fibrosis score and fibronectin, Collagen, and α-SMA expression in bleomycin-induced pulmonary fibrosis mice. In conclusion, MPT0E028 induced MKP-1 acetylation and activation, which in turn inhibited TGF-β-stimulated JNK, p38, and ERK phosphorylation; SMAD3 and AP-1 activation; and subsequent CTGF expression in human lung fibroblasts. Thus, MPT0E028 may be a potential drug for treating pulmonary fibrosis.

Keywords

Connective tissue growth factor (CTGF); MPT0E028; Mitogen-activated protein kinase phosphatase-1 (MKP-1); Pulmonary fibrosis; Transforming growth factor (TGF-β).

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