YAP1 inhibits the senescence of alveolar epithelial cells by targeting Prdx3 to alleviate pulmonary fibrosis

特发性肺纤维化 肺纤维化 雅普1 衰老 博莱霉素 癌症研究 纤维化 细胞生物学 病理 医学 生物 内科学 生物化学 转录因子 基因 化疗
作者
Wei Su,Yingying Guo,Qianqian Wang,Lu Ma,Qing Zhang,Yuhan Zhang,Yiding Geng,Tongzhu Jin,Jiayu Guo,Ruoxuan Yang,Zhihui Niu,Lingxue Ren,Yan Wang,Zhiwei Ning,Wenyue Li,Wenxin He,Jian Sun,Tianyu Li,Zhixin Li,Hongli Shan,Haihai Liang
出处
期刊:Experimental and Molecular Medicine [Springer Nature]
卷期号:56 (7): 1643-1654 被引量:1
标识
DOI:10.1038/s12276-024-01277-0
摘要

Abstract The senescence of alveolar type II (AT2) cells impedes self-repair of the lung epithelium and contributes to lung injury in the setting of idiopathic pulmonary fibrosis (IPF). Yes-associated protein 1 (YAP1) is essential for cell growth and organ development; however, the role of YAP1 in AT2 cells during pulmonary fibrosis is still unclear. YAP1 expression was found to be downregulated in the AT2 cells of PF patients. Deletion of YAP1 in AT2 cells resulted in lung injury, exacerbated extracellular matrix (ECM) deposition, and worsened lung function. In contrast, overexpression of YAP1 in AT2 cells promoted alveolar regeneration, mitigated pulmonary fibrosis, and improved lung function. In addition, overexpression of YAP1 alleviated bleomycin (BLM) -induced senescence of alveolar epithelial cells both in vivo and in vitro. Moreover, YAP1 promoted the expression of peroxiredoxin 3 (Prdx3) by directly interacting with TEAD1. Forced expression of Prdx3 inhibited senescence and improved mitochondrial dysfunction in BLM-treated MLE-12 cells, whereas depletion of Prdx3 partially abrogated the protective effect of YAP1. Furthermore, overexpression of Prdx3 facilitated self-repair of the injured lung and reduced ECM deposition, while silencing Prdx3 attenuated the antifibrotic effect of YAP1. In conclusion, this study demonstrated that YAP1 alleviates lung injury and pulmonary fibrosis by regulating Prdx3 expression to improve mitochondrial dysfunction and block senescence in AT2 cells, revealing a potential novel therapeutic strategy for pulmonary fibrosis.
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