Glycogen synthase kinase-3β: a promising candidate in the fight against fibrosis

Abstract

Fibrosis exists in almost all organs/tissues of the human body, plays an important role in the occurrence and development of diseases and is also a hallmark of the aging process. However, there is no effective prevention or therapeutic method for fibrogenesis. As a serine/threonine (Ser/Thr)-protein kinase, glycogen synthase kinase-3β (GSK-3β) is a vital signaling mediator that participates in a variety of biological events and can inhibit extracellular matrix (ECM) accumulation and the epithelial-mesenchymal transition (EMT) process, thereby exerting its protective role against the fibrosis of various organs/tissues, including the heart, lung, liver, and kidney. Moreover, we further present the upstream regulators and downstream effectors of the GSK-3β pathway during fibrosis and comprehensively summarize the roles of GSK-3β in the regulation of fibrosis and provide several potential targets for research. Collectively, the information reviewed here highlights recent advances vital for experimental research and clinical development, illuminating the possibility of GSK-3β as a novel therapeutic target for the management of tissue fibrosis in the future.

Exogenous Plant gma-miR-159a, Identified by miRNA Library Functional Screening, Ameliorated Hepatic Stellate Cell Activation and Inflammation via Inhibiting GSK-3β-Mediated Pathways

“…Aside from regulating the activity of glycogen synthase, GSK-3β not only acts as an oncogene but also participates in various cellular processes, including cell cycle control, DNA damage and repair, gene transcription, and cell apoptosis. 30 , 31 GSK-3β is associated with the development of numerous human diseases, including Type 2 diabetes, atherosclerosis, cardiomyopathy, fibrosis, aging, infertility, and certain cancers. 31 , 32 Remarkably, GSK-3β activation is involved in the development of human liver cirrhosis, whereas GSK-3β inhibition prevents fibroblast activation and fibrogenesis, resulting in decreased levels of ROS and subsequently inactivating various downstream factors, including mTOR, NF-κB, and TGF-β1 signaling, as well as JAK/STAT3 phosphorylation.…”

Mouse Mesenchymal Stem Cell-derived Exosomal Mir-466f-3p Reverses Emt Process Through Inhibiting Akt/gsk3β Pathway via C-met in Radiation-induced Lung Injury

“…To data, constitutive activity of GSK-3β is a vital signaling mediator that can facilitate the epithelial architecture via a reverse of EMT process, thereby exerting its protective role against the tissue fibrosis [39,40]. Whereas inhibited GSK-3β suppresses the phosphorylation of SNAIL and induces the nuclear localization of SNAIL [41], which subsequently binds to the E-boxes of the E-cadherin promoter and represses its expression [22].…”

Endoplasmic reticulum stress promotes epithelial‑mesenchymal transition via the PERK signaling pathway in paraquat‑induced pulmonary fibrosis

“…GSK-3β, which is required for the maintenance of epithelial architecture, was discovered to serve a fundamental role in EMT (27,56). Snail, an EMT-promoting factors, was found to be negatively regulated by GSK-3β (29)(30)(31)57).…”

“…Previous studies have shown that GSK-3β had an important role in maintaining the epithelial architecture (26)(27)(28). In addition, Snail, one of the key factors regulating EMT, accumulated in the nucleus following the inhibition of GSK-3β (29)(30)(31).…”