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<p>Pulmonary aging is characterized by progressive structural and functional decline. Neddylation is recognized as a crucial mechanism for maintaining cellular homeostasis; however, its function in pulmonary aging has not been fully elucidated. In this study, we found that the core neddylation E2 enzyme UBE2M was downregulated in aged lung tissues. <i>Ube2m</i> knockdown mice exhibited premature pulmonary aging, including vascular degeneration and structural disruption. Notably, in the lungs of knockout mice, although VEGF expression—primarily secreted by epithelial cells—remained unchanged, the protein level and phosphorylation of its receptor VEGFR2 on endothelial cells were significantly reduced. Mechanistic investigation confirmed that UBE2M directly regulates VEGFR2 stability in pulmonary endothelial cells via neddylation. In a doxorubicin-induced endothelial cell senescence model, UBE2M downregulation was accompanied by impaired VEGFR2 signaling, whereas UBE2M reconstitution partially alleviated cellular senescence. In elastase-induced emphysema mouse models and in lung tissues from COPD patients, both UBE2M and VEGFR2 levels were markedly reduced, and Ube2m deficiency exacerbated lung injury. In conclusion, this study demonstrates that UBE2M delays pulmonary aging by stabilizing VEGFR2 through neddylation, suggesting its potential as a therapeutic target for age-related pulmonary diseases.</p><p></p>

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UBE2M-mediated neddylation modification stabilizes VEGFR2 to delay pulmonary vascular endothelial cell senescence

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年5月28日

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  • Yunhao Chang,
  • Qiao Chen,
  • Xia Xu,
  • Xinxing Lyu,
  • Linlin Xu,
  • Qingxia Hu,
  • Yu Han,
  • Yutao Wu,
  • Xiaomeng Zhang,
  • Li Qiao,
  • Zhihao Cai,
  • Shuhong Huang,
  • Jianqing Wu,
  • Bo Chen

摘要

Pulmonary aging is characterized by progressive structural and functional decline. Neddylation is recognized as a crucial mechanism for maintaining cellular homeostasis; however, its function in pulmonary aging has not been fully elucidated. In this study, we found that the core neddylation E2 enzyme UBE2M was downregulated in aged lung tissues. Ube2m knockdown mice exhibited premature pulmonary aging, including vascular degeneration and structural disruption. Notably, in the lungs of knockout mice, although VEGF expression—primarily secreted by epithelial cells—remained unchanged, the protein level and phosphorylation of its receptor VEGFR2 on endothelial cells were significantly reduced. Mechanistic investigation confirmed that UBE2M directly regulates VEGFR2 stability in pulmonary endothelial cells via neddylation. In a doxorubicin-induced endothelial cell senescence model, UBE2M downregulation was accompanied by impaired VEGFR2 signaling, whereas UBE2M reconstitution partially alleviated cellular senescence. In elastase-induced emphysema mouse models and in lung tissues from COPD patients, both UBE2M and VEGFR2 levels were markedly reduced, and Ube2m deficiency exacerbated lung injury. In conclusion, this study demonstrates that UBE2M delays pulmonary aging by stabilizing VEGFR2 through neddylation, suggesting its potential as a therapeutic target for age-related pulmonary diseases.