C/EBPγ Activation of β-Catenin Pathway Through Interaction With C/EBPα In Idiopathic Pulmonary Fibrosis

Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal interstitial lung disease marked by abnormal epithelial-mesenchymal transition (EMT) and fibroblast activation, though the molecular mechanisms driving these processes remain unclear. Here, we report that the CCAAT enhancer binding protein γ (C/EBPγ), a transcription factor, is significantly upregulated in IPF lung tissues, bleomycin-induced fibrotic mouse lungs. C/EBPγ overexpression promoted EMT in A549 cells, as evidenced by decreased E-cadherin, increased N-cadherin and vimentin, alongside enhanced fibroblast migration and fibrotic marker upregulation (Collagen I, fibronectin, and α-SMA) in MRC-5 cells. Mechanistically, C/EBPγ activated β-catenin pathway by stabilizing β-catenin through transcriptional repression of AXIN1, a key component of the degradation complex. This repression occurred via interaction with C/EBPα, antagonizing its promotion of AXIN1 expression, as confirmed by co-immunoprecipitation, immunofluorescence, and rescue experiments. In vivo, adeno-associated virus-mediated C/EBPγ overexpression aggravated pulmonary fibrosis induced by bleomycin in mice, enhancing collagen deposition, inflammation, and β-catenin expression, whereas knockdown alleviated these changes. Collectively, downregulation of C/EBPγ plays significant antifibrotic role via the C/EBPα-AXIN1-β-catenin axis, highlighting its therapeutic potential for IPF intervention.