Background: Idiopathic pulmonary fibrosis (IPF) is a progressive fibrotic lung disease with unknown cause and fewer treatments. Genetic studies link Desmoplakin (DSP) gene variations to increased IPF risk, but mechanisms are unclear.
Aim: To investigate DSP?s role in IPF and the underlying mechanism.
Methods: Effects of DSP knockdown on cellular permeability, pro-fibrotic mediators, epithelial-to-mesenchymal transition (EMT), cell migration, and fibrotic gene expression were evaluated in human alveolar epithelial (A549) cells using lucifer yellow permeability assay, qPCR, Western blot, and scratch wound assay. Pathway enrichment analysis via the STRING database identified mechanisms, confirmed experimentally in DSP knockdown A549 and DSP-overexpressed HEK293 cells through qPCR, Western blot, immunofluorescence, luciferase assays, and Wnt signalling inhibitors. Cycloheximide chase assay examined DSP's regulation of plakoglobin and ?-catenin expression in A549 cells.
Results:DSP loss increased pro-fibrotic mediators, EMT, cell migration, and fibrotic gene expression. Pathway analysis identified Wnt/?-catenin signalling as a key mechanism. DSP suppression reduced plakoglobin (PG) and increased nuclear ?-catenin, enhancing TCF/LEF-dependent transcription and upregulating fibrotic genes (COL1A1, MMP9). DSP loss destabilized desmosomes, promoting PG degradation and reducing ?-catenin degradation. Conversely, DSP overexpression and Wnt/?-catenin pathway inhibition reduced fibrotic gene expression.
Conclusions: DSP acts as an anti-fibrotic factor, with the DSP-PG-Wnt/?-catenin axis playing a crucial role in IPF pathogenesis, suggesting its potential as a therapeutic target.