FNDC5/irisin regulates mitochondrial function in airway subepithelial fibrosis of severe asthma

Severe asthma is characterized by persistent airway inflammation and subepithelial fibrosis. Mitochondrial dysfunction plays a crucial role in bronchial fibroblast differentiation and resistance to apoptosis, exacerbating subepithelial fibrosis. Fibronectin type III domain containing 5 (FNDC5)/irisin plays a crucial role in modulating metabolism and protecting mitochondria during inflammation through AMP-activated protein kinase (AMPK) phosphorylation, potentially alleviating the progression of chronic diseases. AMPK activation induces osteoblast differentiation via the Smad1/5/9 pathway. However, whether TGF-β reduces FNDC5 via the AMPK/smad1/5/9 pathway in normal human lung fibroblasts (NHLFs) remains unknown. This research project aims to explore the role of FNDC5/irisin in alleviating airway subepithelial fibrosis by regulating mitochondrial function in severe asthma. Preliminary data indicated reduced FNDC5 expression in severe asthma bronchial tissue and fibroblasts. Irisin downregulated α-SMA expression dose-dependently, alleviating mitochondrial dysfunction in asthma fibroblasts. FNDC5 expression was decreased in OVA-induced airway fibrosis mice. RNA-sequence analysis showed reduced Fndc5 expression in OVA-induced asthmatic mice. TGF-β decreased FNDC5 expression and AMPK phosphorylation in a time-dependent manner in NHLFs. Moreover, irisin decreased TGF-β-induced α-SMA and fibronectin expression and Smad3 phosphorylation in NHLFs. Additionally, irisin affected mitochondrial-associated cellular components, biological processes, and molecular functions compared to TGF-β-treated NHLFs. Therefore, this research project's central hypothesis is that FNDC5/irisin down-regulates TGF-β-induced mitochondrial dysfunction in subepithelial fibrosis in severe asthma.