Abstract
Idiopathic pulmonary fibrosis (IPF) is a progressive and often fatal lung disease. Despite recent treatment advancements, survival rates for IPF patients remain low, reflecting the urgent need for a deeper understanding of disease mechanisms. A key feature of IPF progression is the excessive growth of fibroblasts and their transformation into myofibroblasts, driven by a profibrotic feed-forward loop involving mediators like transforming growth factor (TGF) α and β1. These factors activate the epidermal growth factor receptor (EGFR) and TGFβ1 receptor (TGFβR1), perpetuating fibrosis. MicroRNAs play a vital role in regulating gene expression, and many are disrupted in IPF. Through RNA sequencing and quantitative RT-PCR, we identified miR-146b as one of the most significantly reduced miRNAs in human lung fibroblasts (HLF) following TGFβ1 treatment, with a confirmed 70% decrease in expression. While miR-146b is normally abundant in lung fibroblasts, its levels are significantly lower in lung fibroblasts from IPF patients (HLF-F) and in mice with experimental pulmonary fibrosis. HLF-F exhibited greater responses to profibrotic signals compared to non-fibrotic fibroblasts (HLF-N). Elevating miR-146b levels in HLF-F reduced TGFα-induced proliferation and inhibited TGFβ1-induced myofibroblast differentiation by 60-90%. Conversely, deletion of the miR-146b gene enhanced fibrotic responses in mouse lung fibroblasts. Additionally, miR-146b directly targets critical signaling pathways, including EGFR, Jun, TGFβR1, and SMAD3, thereby suppressing fibroblast proliferative and fibrogenic activities. Thus, targeting miR-146b presents a promising therapeutic strategy to inhibit lung fibroblast proliferation and differentiation by modulating the profibrotic feedforward loop of EGFR and TGFβR signaling pathways.