MSTN gene knockout suppresses the activation of lung fibroblasts through the inhibition of the Smad/AKT signaling pathway, thereby ameliorating pulmonary fibrosis

Abstract

Pulmonary fibrosis is a chronic interstitial lung disease characterized by irreversible, progressive lung scarring and eventual respiratory failure. Fibroblast activation plays a crucial role in the progression of pulmonary fibrosis. Transforming growth factor-β (TGF-β) signaling contributes to pulmonary fibrosis by regulating lung fibroblast activation. Currently, most studies focus on TGF-β1 regulatory effects on fibroblasts, with limited reports on myostatin (MSTN), another member of the same family. This study used MSTN gene knockout (MSTN^−/−) boars as animal models to explore MSTN regulatory effects on pulmonary fibrosis by modulating lung fibroblast activation. Studies have demonstrated that MSTN is significantly upregulated in the lungs during pulmonary fibrosis, promoting the activation of downstream Smad and AKT signaling pathways. MSTN^−/− inhibits alveolar collapse and interstitial thickening in pulmonary fibrosis pigs and suppresses downstream Smad and AKT signaling. In vitro experiments showed that MSTN^−/− inhibits lung fibroblast activation by blocking Smad/AKT signaling. These findings suggest that the MSTN/Smad/AKT signaling axis suppresses pulmonary fibrosis by inhibiting lung fibroblast activation, indicating that MSTN could be a potential therapeutic target for pulmonary fibrosis.