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

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.