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

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

  • Respir Res. 2025 Apr 9;26(1):128. doi: 10.1186/s12931-025-03201-0.
Junhui Ba # 1,  Changyu Zheng # 2,  Yimei Lai 3,  Xin He 4,  Yuxi Pan 5,  Yanqiu Zhao 6,  Huihui Xie 3,  Benquan Wu 7,  Xiao Deng 8,  Nan Wang 9 10 11
Affiliations

Affiliations

  • 1 Department of Medical Intensive Care Unit, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong Province, China.
  • 2 School of Medicine, Shenzhen Campus of Sun Yat-sen University, Sun Yat-sen University, Shenzhen, Guangdong Province, China.
  • 3 Department of Pathology, The First Affiliated Hospital of Gannan Medical University, Ganzhou, Jiangxi Province, China.
  • 4 Scientific Research Center, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, Guangdong Province, China.
  • 5 Department of Oncology, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, Guangdong Province, China.
  • 6 Shenzhen Samii Medical Center, Shenzhen, Guangdong Province, China.
  • 7 Department of Medical Intensive Care Unit, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong Province, China. wubq@mail.sysu.edu.cn.
  • 8 Department of Pathology, The First Affiliated Hospital of Gannan Medical University, Ganzhou, Jiangxi Province, China. dxpathology@163.com.
  • 9 Scientific Research Center, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, Guangdong Province, China. wangnan@sysush.com.
  • 10 School of Medicine, Shenzhen Campus of Sun Yat-sen University, Sun Yat-sen University, Shenzhen, Guangdong Province, China. wangnan@sysush.com.
  • 11 Shenzhen Key Laboratory of Chinese Medicine Active Substance Screening and Translational Research, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, Guangdong Province, China. wangnan@sysush.com.
  • # Contributed equally.
PMID: 40205454 DOI: 10.1186/s12931-025-03201-0
Abstract

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 the Autophagy lysosome pathway. The use of chloroquine can effectively alleviate cellular senescence.

Conclusions: High matrix stiffness degrades lamin A/C in pulmonary fibrosis through lysosomal degradation pathways, promoting AEC II senescence. Inhibition the degradation of lamin A/C could alleviate AEC II senescence.

Keywords

Cell senescence; Idiopathic pulmonary fibrosis; Lamin A/C.

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