SGK1 mediates TGF-β1-induced epithelial-mesenchymal transition and fibrosis in experimental bronchiolitis obliterans

Bronchiolitis obliterans (BO) represents a major complication limiting long-term survival after lung transplantation, with epithelial-mesenchymal transition (EMT) serving as a core pathogenic mechanism. The TGF-β1 signaling pathway plays a critical role in EMT induction and can activate serum/glucocorticoid-regulated kinase 1 (SGK1) expression. While SGK1 is upregulated in various fibrotic diseases, its functional significance in BO remains undefined. To elucidate SGK1's role in post-transplant BO fibrosis and its interaction with the TGF-β1 pathway, we established a murine heterotopic tracheal transplantation model. Histopathological evaluation and RNA sequencing demonstrated significant SGK1 upregulation in BO lesions by day 28. In vitro , both pharmacological inhibition (EMD638683) and genetic knockdown of SGK1 (siRNA) attenuated TGF-β1-induced EMT in the human small airway epithelial cell line (HSAECs), while concurrently suppressing the expression of extracellular matrix genes (COL1 and FN1). Furthermore, SGK1 inhibition reduced TGF-β1-induced SMAD2/3 phosphorylation. Therapeutic administration of EMD638683, initiated after disease establishment, significantly ameliorated BO pathology. These findings demonstrate that SGK1 promotes BO-associated fibrosis through TGF-β1-mediated EMT and ECM deposition, identifying SGK1 as a potential therapeutic target for post-transplant BO intervention.