Circgrhpr Inhibits Aberrant Epithelial-Mesenchymal Transformation Progression of Lung Epithelial Cells Associated with Idiopathic Pulmonary Fibrosis.

Air pollution has greatly increased the risk of idiopathic pulmonary fibrosis (IPF). Circular RNAs (circRNAs) have been found to play a significant role in the advancement of IPF, but there is limited evidence of correlation between circRNAs and lung epithelial cells (LECs) in IPF. This research aimed to explore the influence of circRNAs on the regulation of EMT progression in LECs, with the objective of elucidating its mechanism and establishing its association with IPF. Our results suggested that the downregulation of circGRHPR in peripheral blood of clinical cases was associated with the diagnosis of IPF. Meanwhile, we found that circGRHPR was downregulated in transforming growth factor-beta1 (TGF-beta 1)-induced A549 and Beas-2b cells. It is a valid model to study the abnormal EMT progression of IPF-associated LECs in vitro. The overexpression of circGRHPR inhibited the abnormal EMT progression of TGF-beta 1-induced LECs. Furthermore, as the sponge of miR-665, circGRHPR released the expression of E3 ubiquitin-protein ligase NEDD4-like (NEDD4L), thus promoting its downstream transforming growth factor beta receptor 2 (TGFBR2) ubiquitination. It is helpful to reduce the response of LECs to TGF-beta 1 signaling. In summary, circGRHPR/miR-665/NEDD4L axis inhibited the abnormal EMT progression of TGF-beta 1-induced LECs by promoting TGFBR2 ubiquitination, which provides new ideas and potential targets for the treatment of IPF.Graphical AbstractGraphical headlights1. Downregulation of circGRHPR in peripheral blood is associated with clinical diagnosis of IPF.2. circGRHPR inhibits the abnormal EMT progression of TGF-beta 1-induced LECs in vitro.3. circGRHPR/miR-665/NEDD4L axis inhibits the abnormal EMT progression of TGF-beta 1-induced LECs by promoting ubiquitination of TGFBR2 in vitro.Graphical AbstractGraphical headlights1. Downregulation of circGRHPR in peripheral blood is associated with clinical diagnosis of IPF.2. circGRHPR inhibits the abnormal EMT progression of TGF-beta 1-induced LECs in vitro.3. circGRHPR/miR-665/NEDD4L axis inhibits the abnormal EMT progression of TGF-beta 1-induced LECs by promoting ubiquitination of TGFBR2 in vitro.Graphical AbstractGraphical headlights1. Downregulation of circGRHPR in peripheral blood is associated with clinical diagnosis of IPF.2. circGRHPR inhibits the abnormal EMT progression of TGF-beta 1-induced LECs in vitro.3. circGRHPR/miR-665/NEDD4L axis inhibits the abnormal EMT progression of TGF-beta 1-induced LECs by promoting ubiquitination of TGFBR2 in vitro.Graphical AbstractGraphical headlights1. Downregulation of circGRHPR in peripheral blood is associated with clinical diagnosis of IPF.2. circGRHPR inhibits the abnormal EMT progression of TGF-beta 1-induced LECs in vitro.3. circGRHPR/miR-665/NEDD4L axis inhibits the abnormal EMT progression of TGF-beta 1-induced LECs by promoting ubiquitination of TGFBR2 in vitro.