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

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.