2. Academic Validation
  3. Doublecortin-like kinase 1 promotes fibroblast activation and fibrotic progression through Smad3 binding in idiopathic pulmonary fibrosis

Doublecortin-like kinase 1 promotes fibroblast activation and fibrotic progression through Smad3 binding in idiopathic pulmonary fibrosis

  • J Biomed Sci. 2026 May 22;33(1):52. doi: 10.1186/s12929-026-01258-7.
Lee-Yuan Lin 1 2,  Wun-Hao Cheng 3,  Yu-Chih Wu 3,  Heng-Ching Wen 3,  Hsao-Hsun Hsu 4 5,  Chia-Hao Liu 1,  Jing-Yun Chen 1,  Wen-Shan Chang 3,  Ying-Jung Wu 2,  Jie-Syuan Wu 2,  Fara Silvia Yuliani 6,  Chueh-Yi Wang 7,  Chien-Huang Lin # 8 9,  Bing-Chang Chen # 10 11 12
Affiliations

Affiliations

  • 1 Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, No. 250, Wuxing St., Xinyi Dist., Taipei, 110, Taiwan.
  • 2 School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.
  • 3 School of Respiratory Therapy, College of Medicine, Taipei Medical University, No. 250, Wuxing St., Xinyi Dist., Taipei, 110, Taiwan.
  • 4 National Taiwan University Hospital & College of Medicine, National Taiwan University, Taipei, Taiwan.
  • 5 Department of Surgical Oncology, National Taiwan University Cancer Center, Taipei, Taiwan.
  • 6 Department of Pharmacology and Therapy, Faculty of Medicine, Public Health, and Nursing, Universitas Gadjah Mada, Yogyakarta, Indonesia.
  • 7 Laboratory Animal Center, Taipei Medical University, Taipei, Taiwan.
  • 8 Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, No. 250, Wuxing St., Xinyi Dist., Taipei, 110, Taiwan. [email protected].
  • 9 Chen Wei-Tien Research Center of Thoracic Medicine, Taipei Medical University, Taipei, Taiwan. [email protected].
  • 10 Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, No. 250, Wuxing St., Xinyi Dist., Taipei, 110, Taiwan. [email protected].
  • 11 School of Respiratory Therapy, College of Medicine, Taipei Medical University, No. 250, Wuxing St., Xinyi Dist., Taipei, 110, Taiwan. [email protected].
  • 12 Chen Wei-Tien Research Center of Thoracic Medicine, Taipei Medical University, Taipei, Taiwan. [email protected].
  • # Contributed equally.
PMID: 42174588 DOI: 10.1186/s12929-026-01258-7
Abstract

Background: Idiopathic pulmonary fibrosis (IPF) is a progressive, fatal lung disease with limited treatment options. Although the results of a gene expression analysis revealed that lung tissues in individuals with IPF contain high levels of doublecortin-like kinase 1 (DCLK1), the role of DCLK1 in fibroblast activation remains unclear. The present study examined the function of DCLK1 in IPF and bleomycin-induced pulmonary fibrosis, exploring its potential as a therapeutic target warranting further investigation.

Methods: We investigated the role of DCLK1 in fibroblast activation and pulmonary fibrosis in lung tissues from patients with IPF, a bleomycin-induced pulmonary fibrosis mouse model, and cultured normal human lung fibroblasts. DCLK1 knockout mice and mice treated with the selective DCLK1 inhibitor DCLK1-IN-1 were used to evaluate the effects of genetic DCLK1 deficiency and pharmacological DCLK1 inhibition on fibrotic progression and lung function.

Results: DCLK1 was markedly upregulated in the IPF lung tissues and in bleomycin-induced fibrotic lung tissues. Global deletion of Dclk1 considerably attenuated fibrotic remodeling and preserved lung function in mice. In addition, transforming growth factor β (TGF-β) induced DCLK1 expression in normal human lung fibroblasts through SMAD3 and NF-κB signaling, while Akt/DCLK1/SMAD3 signaling was associated with fibroblast activation and profibrotic marker expression. Moreover, DCLK1 was associated with SMAD3, and these findings were consistent with DCLK1-Smad3-associated signaling linked to connective tissue growth factor expression. Finally, oral administration of DCLK1-IN-1 slowed fibrotic progression and preserved lung function in bleomycin-treated mice.

Conclusions: DCLK1 is associated with fibroblast activation and pulmonary fibrosis, with findings consistent with DCLK1-Smad3-associated signaling linked to profibrotic marker expression. Genetic deletion or pharmacological inhibition of DCLK1 attenuated fibrotic progression and preserved lung function, suggesting that DCLK1 warrants further investigation as a potential therapeutic target in pulmonary fibrosis.

Keywords

DCLK1; Fibroblasts; Idiopathic Pulmonary Fibrosis; Smad3; TGF-β.

Figures
Products