Multiomics Integration Reveals Distinct miRNA-Mediated Regulatory Networks at the Transcript and Protein Levels in Idiopathic Pulmonary Fibrosis

Abstract

MicroRNAs (miRNAs) are key post-transcriptional regulators implicated in multilevel molecular dysregulation in idiopathic pulmonary fibrosis (IPF). However, their function is largely inferred from miRNA–mRNA associations, leaving protein-level consequences poorly defined. We performed an integrated multiomics analysis combining miRNA sequencing, RNA sequencing, and proteomic profiling of primary lung fibroblasts from patients with IPF and controls. Transcriptomic data were obtained from the Gene Expression Omnibus (GSE301181), and donor-matched proteomic data were deposited in Figshare. miRNA–mRNA correlations and miRNA–protein associations were evaluated through integrative correlation and interaction analyses, followed by functional enrichment and network modeling. Thirteen differentially expressed miRNAs were identified and showed widespread negative correlations with 710 differentially expressed genes. In contrast, proteomic integration identified a more restricted subset of 229 miRNA-associated differentially expressed proteins. Functional enrichment revealed broad distribution of miRNA–mRNA associations across extracellular matrix organization, immune signaling, and cell migration pathways, whereas miRNA–protein associations converged on a limited set of biological processes with higher enrichment ratios. Several miRNAs were linked to known fibrosis- and stress-related targets, supporting biological relevance. Together, these findings suggest that integrated protein-level analysis helps refine fibrosis-relevant miRNA regulatory programs in IPF fibroblasts and may improve biological interpretation of disease-associated molecular changes.