High matrix stiffness promotes senescence of type II alveolar epithelial cells by lysosomal degradation of lamin A/C in pulmonary fibrosis

作者：Junhui Ba, Changyu Zheng, Yimei Lai, Xin He, Yuxi Pan, Yanqiu Zhao, Huihui Xie, Benquan Wu, Xiao Deng, Nan Wang · 发表于：Respiratory Research · 年份：2025 · DOI：10.1186/s12931-025-03201-0 · 被引用次数：10 · 研究领域：Neonatal Respiratory Health Research、Nuclear Structure and Function、Telomeres, Telomerase, and Senescence

BACKGROUND: Cellular senescence is one of the key steps in the progression of pulmonary fibrosis, and the senescence of type II alveolar epithelial cells (AEC IIs) may potentially accelerate the progression of pulmonary fibrosis. However, the molecular mechanisms underlying cellular senescence in pulmonary fibrosis remain unclear. METHODS: The researchers first conducted in vitro experiments to investigate whether AEC IIs cultured on high matrix stiffness would lead to cellular senescence. Next, samples from mouse pulmonary fibrosis models and clinical idiopathic pulmonary fibrosis (IPF) patients were tested to observe extracellular matrix deposition, lamin A/C levels, and cellular senescence status in lung tissue. Construct lamin A/C knockdown and overexpression systems separately in AEC IIs, and observe whether changes in lamin A/C levels lead to cellular senescence. Further explore the degradation mechanism of lamin A/C using protein degradation inhibitors. RESULTS: In vitro experiments have found that high matrix stiffness promotes senescence of AEC IIs. In a mouse model of pulmonary fibrosis, AEC IIs were found to exhibit significant cellular senescence on day 21. In clinical IPF samples, it was found that senescent cells expressed low levels of lamin A/C. In the lamin A/C SiRNA knockdown system, it was further confirmed that AEC IIs with low levels of lamin A/C are more prone to cellular senescence. Under high matrix stiffness, lamin A/C in AEC IIs is degraded through t...