Guo Jiayu, Wang Yan, Liu Qiudi, Luo Zhaoyang, Tian Xiaomu, Wang Yuquan, Liu Yang, Ning Zhiwei, Guo Yingying, Gao Huiying, Wang Xinyue, Feng Jinglong, Liu Mengmeng, Saifullina Dina, Zhang Yixin, Pan Tengfei, Bian Yu, Ban Tao, Li Tianyu, Gu Yunyan, Liang Haihai
State Key Laboratory of Frigid Zone Cardiovascular Diseases (SKLFZCD), Department of Pharmacology (State Key Laboratory-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, 150081, China.
Department of Systems Biology, College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, 150081, China.
Adv Sci (Weinh). 2025 Aug;12(32):e01956. doi: 10.1002/advs.202501956. Epub 2025 May 30.
Idiopathic pulmonary fibrosis (IPF) is a prototype of chronic, progressive, and fibrotic lung disease. While advancing age is recognized as the most significant risk factor for both the development and mortality associated with pulmonary fibrosis, precise mechanisms underlying this association remain elusive. Here, Nephronectin (NPNT) is identified as an antiaging molecule, a potential major regulator of the progression of pulmonary fibrosis. In IPF patients, a marked reduction in NPNT expression is detected in lung tissues, which correlated with a decline in lung function. The study reveals that NPNT deficiency exacerbates bleomycin-induced senescence in alveolar epithelial cells, potentially intensifying fibrosis severity due to diminishes extracellular matrix turnover. Conversely, NPNT overexpression in the alveolar epithelium improves lung respiratory function and enhances resistance to aging and fibrosis. Mechanistically, NPNT inhibits the hyperactivation of LATS1 and MOB1, facilitates YAP1 nuclear translocation, and suppresses YAP1 ubiquitination and degradation, contingent upon the interaction between NPNT and ITGA3. Notably, pharmacological elevation of NPNT protein levels using Escin has been shown to alleviate pulmonary fibrosis and improve lung function in mice. The findings shed light on the key mechanism underlying stress-induced senescence and fibrosis, and offer a promising framework for interventions targeting aging-related diseases.
特发性肺纤维化（IPF）是慢性、进行性和纤维化肺部疾病的典型代表。虽然年龄增长被认为是与肺纤维化发生和死亡相关的最重要风险因素，但这种关联背后的确切机制仍不清楚。在此，肾连蛋白（NPNT）被鉴定为一种抗衰老分子，是肺纤维化进展的潜在主要调节因子。在IPF患者中，肺组织中检测到NPNT表达显著降低，这与肺功能下降相关。该研究表明，NPNT缺乏会加剧博来霉素诱导的肺泡上皮细胞衰老，可能由于细胞外基质周转减少而加剧纤维化严重程度。相反，肺泡上皮中NPNT的过表达可改善肺呼吸功能，并增强对衰老和纤维化的抵抗力。从机制上讲，NPNT抑制LATS1和MOB1的过度激活，促进YAP1核转位，并抑制YAP1的泛素化和降解，这取决于NPNT与ITGA3之间的相互作用。值得注意的是，已证明使用七叶皂苷药理上调NPNT蛋白水平可减轻小鼠肺纤维化并改善肺功能。这些发现揭示了应激诱导衰老和纤维化的关键机制，并为针对衰老相关疾病的干预提供了一个有前景的框架。
