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Background <p>Obesity is a major risk factor for chronic obstructive pulmonary disease (COPD); however, the precise molecular pathways remain poorly defined, and it is uncertain whether severe obesity by itself can trigger COPD-like pathology. PLA2G7 has been identified as a pathogenic gene in COPD, yet the molecular mechanisms by which PLA2G7 contributes to disease development remain to be elucidated.</p> Methods <p>To investigate the role of PLA2G7 in obesity-related chronic obstructive pulmonary disease (COPD), we employed clinical specimens as well as in vivo and in vitro models, integrating multi-omics approaches with genetic and pharmacological interventions. Key methodologies included protein and gene expression analyses (Western blotting,, immunohistochemistry, ELISA assay, qRT-PCR), assessment of oxidative stress and lipid peroxidation (ROS and BODIPY staining), histological evaluation (H&amp;E Staining, Oil Red O Staining, AB-PAS staining), transmission electron microscopy, micro-computed tomography (micro-CT), and pulmonary function tests in mice. Furthermore, molecular docking and molecular dynamics simulations were performed to explore potential molecular interactions of PLA2G7.</p> Results <p>Using a diet-induced obesity model, this study revealed that obesity alone elicits COPD-like pulmonary changes, defined by weight-dependent alveolar injury, elevated airway mucus secretion, and reduced lung function. Transcriptomic analysis of lung tissues from obesity-associated COPD patients and obese mice identified macrophage-derived phospholipase A2 group VII (<i>PLA2G7</i>) as a key regulator of disease pathogenesis. Genetic deletion or pharmacological suppression of <i>PLA2G7</i> was found to reduce obesity-associated COPD-like pathology. Mechanistically, high-fat stimulation induced upregulation of <i>PLA2G7</i> in macrophages, leading to increased release of arachidonic acid (AA). The higher AA levels promoted the accumulation of lipid-derived reactive oxygen species (ROS) and stabilized <i>NLRP3</i> mRNA by reducing its degradation. This process activated the inflammasome and triggered pyroptosis, thus driving pulmonary inflammation and contributing to COPD development.</p> Conclusions <p><i>PLA2G7</i> acts as a key mediator of obesity-associated COPD and represents a promising therapeutic target for preventing obesity-related lung injury.</p>

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Targeting PLA2G7 ameliorates high-fat diet–induced pulmonary injury in obese mice, uncovering a key mechanistic link to obesity-associated COPD

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年2月6日

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  • Zhi-Heng Li,
  • Mei-Yu Lv,
  • Xin Zhang,
  • Bao-cai Wang,
  • Yao Wang,
  • Li-Xia Qiang,
  • Xiangshun Li,
  • Wenchao Shi,
  • Xin-yu Guo,
  • Xi-Qiao Sang

摘要

Background

Obesity is a major risk factor for chronic obstructive pulmonary disease (COPD); however, the precise molecular pathways remain poorly defined, and it is uncertain whether severe obesity by itself can trigger COPD-like pathology. PLA2G7 has been identified as a pathogenic gene in COPD, yet the molecular mechanisms by which PLA2G7 contributes to disease development remain to be elucidated.

Methods

To investigate the role of PLA2G7 in obesity-related chronic obstructive pulmonary disease (COPD), we employed clinical specimens as well as in vivo and in vitro models, integrating multi-omics approaches with genetic and pharmacological interventions. Key methodologies included protein and gene expression analyses (Western blotting,, immunohistochemistry, ELISA assay, qRT-PCR), assessment of oxidative stress and lipid peroxidation (ROS and BODIPY staining), histological evaluation (H&E Staining, Oil Red O Staining, AB-PAS staining), transmission electron microscopy, micro-computed tomography (micro-CT), and pulmonary function tests in mice. Furthermore, molecular docking and molecular dynamics simulations were performed to explore potential molecular interactions of PLA2G7.

Results

Using a diet-induced obesity model, this study revealed that obesity alone elicits COPD-like pulmonary changes, defined by weight-dependent alveolar injury, elevated airway mucus secretion, and reduced lung function. Transcriptomic analysis of lung tissues from obesity-associated COPD patients and obese mice identified macrophage-derived phospholipase A2 group VII (PLA2G7) as a key regulator of disease pathogenesis. Genetic deletion or pharmacological suppression of PLA2G7 was found to reduce obesity-associated COPD-like pathology. Mechanistically, high-fat stimulation induced upregulation of PLA2G7 in macrophages, leading to increased release of arachidonic acid (AA). The higher AA levels promoted the accumulation of lipid-derived reactive oxygen species (ROS) and stabilized NLRP3 mRNA by reducing its degradation. This process activated the inflammasome and triggered pyroptosis, thus driving pulmonary inflammation and contributing to COPD development.

Conclusions

PLA2G7 acts as a key mediator of obesity-associated COPD and represents a promising therapeutic target for preventing obesity-related lung injury.