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-β1)–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-β1-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-β1 signaling. In summary, circGRHPR/miR-665/NEDD4L axis inhibited the abnormal EMT progression of TGF-β1-induced LECs by promoting TGFBR2 ubiquitination, which provides new ideas and potential targets for the treatment of IPF.

Graphical Abstract

Graphical headlights

1. Downregulation of circGRHPR in peripheral blood is associated with clinical diagnosis of IPF.

2. circGRHPR inhibits the abnormal EMT progression of TGF-β1-induced LECs in vitro.

3. circGRHPR/miR-665/NEDD4L axis inhibits the abnormal EMT progression of TGF-β1-induced LECs by promoting ubiquitination of TGFBR2 in vitro.

中文翻译：

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circGRHPR抑制与特发性肺纤维化相关的肺上皮细胞异常上皮间质转化进程

空气污染大大增加了特发性肺纤维化（IPF）的风险。环状RNA（circRNA）已被发现在IPF的进展中发挥重要作用，但circRNA与IPF中肺上皮细胞（LEC）之间相关性的证据有限。本研究旨在探讨circRNA对LECs EMT进展调控的影响，旨在阐明其机制并建立其与IPF的关联。我们的结果表明，临床病例外周血中circGRHPR的下调与IPF的诊断相关。同时，我们发现 circGRHPR 在转化生长因子-β1 (TGF-β1) 诱导的 A549 和 Beas-2b 细胞中下调。它是体外研究IPF相关LEC异常EMT进展的有效模型。circGRHPR 的过表达抑制了 TGF-β1 诱导的 LEC 的异常 EMT 进展。此外，作为miR-665的海绵，circGRHPR释放E3泛素蛋白连接酶NEDD4-like（NEDD4L）的表达，从而促进其下游转化生长因子β受体2（TG​​FBR2）泛素化。有助于降低LECs对TGF-β1信号传导的反应。综上所述，circGRHPR/miR-665/NEDD4L轴通过促进TGFBR2泛素化抑制TGF-β1诱导的LECs异常EMT进展，这为IPF的治疗提供了新思路和潜在靶点。

图形概要

图形车头灯

1.外周血circGRHPR下调与IPF的临床诊断相关。

2. circGRHPR在体外抑制TGF-β1诱导的LECs异常EMT进展。

3. circGRHPR/miR-665/NEDD4L轴在体外通过促进TGFBR2泛素化抑制TGF-β1诱导的LECs异常EMT进展。