Abstract
BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a type of interstitial lung disease that is critically influenced by epigenetic regulation and mitochondrial function during its pathogenesis and progression. Flavonoids possess significant anti-inflammatory and antioxidant properties, and among these compounds, quercetin has been shown to inhibit the progression of pulmonary fibrosis by modulating the expression of specific microRNAs (miRNAs) and alleviating oxidative stress associated with mitochondrial dysfunction. However, the precise underlying mechanism remains unclear. METHODS: We established a murine model of pulmonary fibrosis via endotracheal nebulization with bleomycin, which resulted in uniformly distributed, severe fibrotic lesions in the lungs. Quercetin (Que) was administered via the intratracheal route, enabling targeted pulmonary delivery, reducing the required drug concentration, increasing bioavailability, and minimizing potential systemic toxicity. For the assessment of histopathological changes and collagen deposition in lung tissues, we used hematoxylin-eosin (H&E) and Masson's trichrome staining. In cell experiments, we stimulated A549 cells with transforming growth factor-β1 (TGF-β1) and transfected them with a miR-423-5p inhibitor to examine the expression levels of extracellular matrix (ECM) related proteins and the NDUFS7 subunit of mitochondrial complex I. Furthermore, we evaluated mitochondrial function by measuring reactive oxygen species (ROS) production, adenosine triphosphate (ATP) content, hydrogen peroxide (H(2)O(2)) levels, and the mitochondrial membrane potential. RESULTS: Our research revealed that quercetin regulated the level of miR-423-5p in mouse lung tissue, as well as the expression of the mitochondrial complex I subunit NDUFS7. After 15 days of endotracheal nebulization with quercetin, extracellular matrix remodeling and collagen deposition in mouse lung tissue were alleviated, and the pulmonary fibrosis induced by bleomycin was improved. In vitro experiments demonstrated that inhibiting miR-423-5p enabled the normal translation and expression of NDUFS7, and improves mitochondrial function, ultimately alleviating the ECM remodeling induced by TGF-β1. CONCLUSION: Targeting miR-423-5p to modulate NDUFS7 expression represents a potential therapeutic strategy for ameliorating mitochondrial dysfunction and suppressing pulmonary fibrosis.