Plasma extracellular vesicles-derived MicroRNAs as potential biomarkers in idiopathic pulmonary fibrosis

Idiopathic pulmonary fibrosis (IPF) is a progressive fibrotic lung disease with limited treatment options. Despite antifibrotic therapies, IPF prognosis remains poor, with a variable clinical course. IPF pathogenesis involves recurrent epithelial injury, dysregulated wound healing, and fibroblast activation, leading to excessive extracellular matrix deposition. MicroRNAs (miRNAs) are small regulatory RNAs that modulate gene expression and have been implicated in fibrotic pathways. Encapsulated within plasma-derived extracellular vesicles (EVs), miRNAs are stabilized and transported through the bloodstream, enabling non-invasive access to disease biomarkers for lung pathology. Plasma samples were obtained from 25 patients with IPF and 8 healthy controls, and the expression of plasma-derived EV miRNAs was analyzed using small RNA sequencing. The functional roles of selected miRNAs were further investigated in human alveolar epithelial cells (A549) and human normal lung fibroblast cells (NHLF) through in vitro experiments. EV miRNA levels were significantly elevated in patients with IPF. Differential expression analysis revealed upregulation of miR-146b-5p, miR-182-5p, and miR-199a-3p and downregulation of miR-92a-3p in the IPF group. Pathway analysis of predicted target genes indicated enrichment in biological processes relevant to IPF pathogenesis, including epithelial proliferation, wound healing, Wnt signaling, and immune regulation. In vitro experiments further demonstrated that overexpression of plasma-derived EV miRNAs modulated fibrogenic marker expression by either enhancing or suppressing TGF-β signaling, depending on the specific miRNA. These findings indicate that the identified miRNAs might be involved in fibrotic responses in lung resident cells and may have potential as non-invasive biomarkers, providing preliminary mechanistic insights into the pathogenesis of IPF.