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Interception of Regulatory RNAs on TGF-β Signaling in the Pathogenesis of Idiopathic Pulmonary Fibrosis: A Systematic Review
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DOI：10.1007/s11882-026-01276-3.png)
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Abstract
En 中文
Idiopathic Pulmonary Fibrosis is a type of interstitial lung disease characterized by lung scarring due to excessive extracellular matrix (ECM) deposition. The transforming growth factor-beta (TGF-β) signaling pathway is the master regulator of fibrosis, driving myofibroblast activation and differentiation, epithelial-mesenchymal transition (EMT), and inhibition of ECM degradation. While individual classes of non-coding RNAs (ncRNAs) have been studied in IPF, a comprehensive understanding of how microRNAs (miRNAs), circular RNAs (circRNAs), and long non-coding RNAs (LncRNAs) collectively regulate canonical TGF-β signaling remains lacking. Addressing this gap, this systematic review was conducted which presents current evidence on the integrated roles of ncRNAs in modulating TGF-β signaling in IPF pathogenesis. A comprehensive search of PubMed and Web of Science databases (2015–2025), identified 45 eligible studies. miRNAs (19 antifibrotic, 11 profibrotic) directly targeted the core components of the TGF-β signaling pathway, whereas circRNAs (5 antifibrotic, 5 profibrotic) and LncRNAs (6 profibrotic) acted as competing endogenous RNAs and sponged their target miRNAs. Notably, all identified LncRNAs were profibrotic, amplifying the fibrotic signaling pathway. We found that ncRNAs critically fine-tune TGF-β signaling at multiple regulatory nodes, including ligand activation, receptor expression, Smad protein phosphorylation, nuclear translocation, and inhibitory feedback mechanism. The ncRNA-mediated regulatory mechanisms provide valuable insight into IPF pathogenesis and may help identify potential biomarkers and therapeutic targets. Future efforts should prioritize validating in vitro and animal model data in human samples, integrating regulatory network analysis, in vivo functional validation of RNA-based therapeutics, and exploring therapeutic delivery systems to develop an effective ncRNA-based antifibrotic therapy.
Keywords:
Idiopathic Pulmonary Fibrosis
Transforming growth factor beta
Smad signaling
MicroRNA
Circular RNA
Long non coding RNA
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