Revisiting the role of MicroRNAs in the pathogenesis of idiopathic pulmonary fibrosis

Abstract

Idiopathic pulmonary fibrosis (IPF) is a prevalent chronic pulmonary fibrosis disease characterized by alveolar epithelial cell damage, fibroblast proliferation and activation, excessive extracellular matrix deposition, and abnormal epithelial-mesenchymal transition (EMT), resulting in tissue remodeling and irreversible structural distortion. The mortality rate of IPF is very high, with a median survival time of 2-3 years after diagnosis. The exact cause of IPF remains unknown, but increasing evidence supports the central role of epigenetic changes, particularly microRNA (miRNA), in IPF. Approximately 10% of miRNAs in IPF lung tissue exhibit differential expression compared to normal lung tissue. Diverse miRNA phenotypes exert either a pro-fibrotic or anti-fibrotic influence on the progression of IPF. In the context of IPF, epigenetic factors such as DNA methylation and long non-coding RNAs (lncRNAs) regulate differentially expressed miRNAs, which in turn modulate various signaling pathways implicated in this process, including transforming growth factor-β1 (TGF-β1)/Smad, mitogen-activated protein kinase (MAPK), and phosphatidylinositol-3-kinase/protein kinase B (PI3K/AKT) pathways. Therefore, this review presents the epidemiology of IPF, discusses the multifaceted regulatory roles of miRNAs in IPF, and explores the impact of miRNAs on IPF through various pathways, particularly the TGF-β1/Smad pathway and its constituent structures. Consequently, we investigate the potential for targeting miRNAs as a treatment for IPF, thereby contributing to advancements in IPF research.

Keywords: IPF; MAPK; PI3K/AKT; TGF-β1/Smad; miRNA.

FIGURE 1

The process of miRNA formation. The biogenesis of miRNAs initiates in the cell nucleus and culminates in the cytoplasm. Mature miRNAs can be categorized into anti-fibrotic miRNAs and pro-fibrotic miRNAs, which modulates fibrogenesis. In this representation, blue denotes inhibitory effects, red arrows signify promoting effects, and orange arrows depict reaction processes. This figure is created by Figdraw. Abbreviations: TGF-β1, transforming growth factor-β1; TβR, TGF-β receptor; DGCR8, DiGeorge Syndrome Critical Region 8; RISC, miRNA-induced silencing complex; Ago, Argonaute; TRBP, transactivation response element RNA-binding protein; PACT, protein activator of protein kinase R.

FIGURE 2

The regulatory of miRNAs expression in IPF. The regulation of miRNAs in IPF is modulated by various epigenetic mechanisms, including DNA methylation, long non-coding RNAs (lncRNAs), circular RNAs (circRNAs), and the miRNAs themselves, with the parentheses denoting those miRNAs that are regulated by these mechanisms. Abbreviations: IPF, idiopathic pulmonary fibrosis; DNMT, DNA methyltransferase; Drp-1, dynamin-related protein-1.

FIGURE 3

The various signaling pathways activated by TGF-β1 stimulation and their partial cross-talk are outlined. The TGF-β1/Smad pathway is initiated when the TGF-β1 ligand binds to its receptors on the cell membrane, leading to the phosphorylation of Smad2/3 proteins. These phosphorylated Smads subsequently associate with Smad4 to form a trimeric complex that translocates into the nucleus, where it regulates the transcription and translation of fibrosis-related genes, thereby inducing EMT. Concurrently, TGF-β receptors recruit ShcA to initiate downstream signaling mediators Grb2 and SOS, thereby activating the Ras, Raf, MEK, and ERK pathways. Furthermore, TGF-β receptors can simultaneously activate the JNK and PI3K/AKT pathways via TRAF6. Likewise, in the pathogenesis of IPF, miRNAs not only regulate the TGF-β1/Smad signaling pathway but also serve as regulatory factors within this pathway. Additionally, they can interconnect the MAPK and PI3K/AKT pathways, thereby establishing a complex regulatory network that sustains the pathological phenotype. This may open new avenues for utilizing miRNAs as more specific therapeutic agents for IPF. This figure is created by Figdraw.