Rationale: Genetic association studies have identified rs2076295 in association with idiopathic pulmonary fibrosis (IPF). We hypothesized rs2076295 is the functional variant regulating desmoplakin (DSP) expression in human bronchial epithelial cells, and DSP regulates extracellular matrix-related gene expression and cell migration, relevant to IPF development.Objective: To determine whether rs2076295 regulates DSP expression, and the function of DSP in airway epithelial cells.Methods: Using CRISPR/Cas9 editing (including regional deletion, indel, CRISPRi, and single-base editing), we modified rs2076295 and measured DSP expression in edited 16HBE14o- and primary airway epithelial cells. Cellular integrity, migration, and genome-wide gene expression changes were examined in 16HBE14o- single colonies with DSP knockout. Expression of DSP and its relevant matrix genes were measured by RT-PCR and also analyzed in single-cell RNA-seq data from control and IPF lungs.Measurements and main results: DSP is expressed predominantly in bronchial and alveolar epithelial cells with reduced expression in alveolar epithelial cells in IPF lungs. Deletion of the DNA region spanning rs2076295 led to reduced expression of DSP and edited rs2076295GG 16HBE14o- line has lower expression of DSP than rs2076295TT lines. Knockout of DSP in 16HBE14o- cells decreased transepithelial resistance but increased cell migration with increased expression of extracellular matrix-related genes, including MMP7 and MMP9. Silencing of MMP7 and MMP9 abolished increased migration in DSP knockout cells.Conclusions: Rs2076295 regulates DSP expression in human airway epithelial cells. Loss of DSP enhances ECM-related gene expression and promotes cell migration, which may contribute to the pathogenesis of idiopathic pulmonary fibrosis.