FNDC5/Irisin Attenuates TGF-β-induced Fibroblast Differentiation Via AMPK/Nrf2 Signaling and Mitochondrial Stabilization in Subepithelial Fibrosis

Severe asthma is characterized by subepithelial fibrosis and mitochondrial dysfunction in bronchial fibroblasts. Fibronectin type III domain-containing 5 (FNDC5)/irisin modulates metabolism and protects mitochondria during inflammation, but its role in fibroblast differentiation remains unclear. In this study, we assessed FNDC5 expression in bronchial tissues from house dust mite (HDM)–induced asthmatic mice and controls by immunohistochemistry, analyzed fibrotic proteins by Western blotting, performed RNA sequencing to identify antioxidant pathway–associated genes, evaluated mitochondrial function using JC-1 staining, and measured airway hyperresponsiveness (AHR) with the FlexiVent system. FNDC5 levels were reduced in asthma-derived lung fibroblasts and in HDM-induced asthmatic mice compared to controls. Treatment with irisin decreased α-SMA expression, improved mitochondrial function, and suppressed TGF-β–induced fibrotic protein expression and Smad3 phosphorylation in human lung fibroblasts. RNA sequencing confirmed that irisin enhanced antioxidant-related gene expression and activated the AMPK pathway, which in turn reduced TGF-β–induced Smad3 phosphorylation and fibronectin expression. Moreover, irisin induced Nrf2 phosphorylation, and Nrf2 knockdown diminished its protective effects on fibrosis markers. In vivo, irisin treatment alleviated HDM-induced airway fibrosis, inflammation, and lung function impairments. Together, these findings demonstrate that FNDC5/irisin protects against airway fibrosis in patients with asthma by activating AMPK and Nrf2 signaling pathways, thereby preserving mitochondrial function and reducing fibroblast differentiation, highlighting FNDC5/irisin as a potential therapeutic target for airway remodeling in asthma.