Abstract
Fibrosis, a major cause of morbidity and mortality, is a histopathological manifestation of many chronic inflammatory diseases affecting different systems of the human body. Two types of transforming growth factor beta (TGF-β) signaling pathways regulate fibrosis: the canonical TGF-β signaling pathway, represented by SMAD-2 and SMAD-3, and the noncanonical pathway, which functions without SMAD-2/3 participation and currently includes TGF-β/mitogen-activated protein kinases, TGF-β/SMAD-1/5, TGF-β/phosphatidylinositol-3-kinase/Akt, TGF-β/Janus kinase/signal transducer and activator of transcription protein-3, and TGF-β/rho-associated coiled-coil containing kinase signaling pathways. MicroRNA (miRNA), a type of non-coding single-stranded small RNA, comprises approximately 22 nucleotides encoded by endogenous genes, which can regulate physiological and pathological processes in fibrotic diseases, particularly affecting organs such as the liver, the kidney, the lungs, and the heart. The aim of this review is to introduce the characteristics of the canonical and non-canonical TGF-β signaling pathways and to classify miRNAs with regulatory effects on these two pathways based on the influenced organ. Further, we aim to summarize the limitations of the current research of the mechanisms of fibrosis, provide insights into possible future research directions, and propose therapeutic options for fibrosis.
Highlights
Fibrosis is a histopathological manifestation of many chronic inflammatory diseases (Wynn, 2007)
Yang et al reported that the low expression of miR-375-3p in the mouse liver can induce the JAK2/signal transducer and activator of transcription protein-3 (STAT3) pathway to activate the TGF-β1/SMAD signal and promote epithelial to mesenchymal transition (EMT), whereas the addition of miR-375-3p mimic has an antifibrotic effect (Yang et al, 2019). These findings indicate the active regulatory functions of miRNAs in liver fibrosis affected by the non-canonical TGF-β signaling pathway
Previous studies have suggested that the TGF-β signaling pathway, which plays a major regulatory role in fibrotic diseases, is widely regulated by miRNAs
Summary
Fibrosis is a histopathological manifestation of many chronic inflammatory diseases (Wynn, 2007). Some fibroproliferative diseases, such as progressive kidney disease, hepatitis, pulmonary fibrosis, cardiovascular disease, scleroderma, and systemic sclerosis, eventually cause high morbidity and mortality by influencing diverse systems of the human body (Wynn, 2007). Fibrosis is characterized by the undue aggregation of extracellular interstitial constituents in and around injured or inflamed tissues, such as collagen and fibronectin (Wynn, 2008). Factors causing fibrotic diseases are genetic, inflammatory, environmental, etc. (Wynn, 2008) Research is underway for the molecular mechanism of fibrotic diseases and valid treatments to prevent or reverse the progression of these diseases (Wynn, 2008; Meng et al, 2016).
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