2. Academic Validation
  3. Extracellular vesicle-packaged GBP2 from macrophages aggravates sepsis-induced acute lung injury by promoting ferroptosis in pulmonary vascular endothelial cells

Extracellular vesicle-packaged GBP2 from macrophages aggravates sepsis-induced acute lung injury by promoting ferroptosis in pulmonary vascular endothelial cells

  • Redox Biol. 2025 May:82:103614. doi: 10.1016/j.redox.2025.103614.
Zhixi Li 1,  Yue Bu 2,  Cheng Wang 3,  Yongjing Yu 1,  Lei Han 4,  Chang Liu 5,  Guangmin Chen 6,  Chenglong Li 7,  Yan Zhang 4,  Hang Cao 4,  Zhaoxue Ma 4,  Ziyong Yue 8
Affiliations

Affiliations

  • 1 Department of Anesthesiology, Second Affiliated Hospital of Harbin Medical University, Harbin, 150001, PR China; The Key Laboratory of Anesthesiology and Intensive Care Research of Heilongjiang Province, Harbin, 150001, PR China; The Key Laboratory of Myocardial Ischemia Organization, Chinese Ministry of Education, Harbin, 150001, PR China; State Key Laboratory of Frigid Zone Cardiovascular Diseases, Harbin, 150001, PR China.
  • 2 Department of Anesthesiology, Second Affiliated Hospital of Harbin Medical University, Harbin, 150001, PR China; The Key Laboratory of Anesthesiology and Intensive Care Research of Heilongjiang Province, Harbin, 150001, PR China; Department of Pain Medicine, Second Affiliated Hospital of Harbin Medical University, Harbin, 150001, PR China.
  • 3 Department of Environmental Hygiene, School of Public Health, Harbin Medical University, Harbin, 150081, PR China.
  • 4 Department of Anesthesiology, Second Affiliated Hospital of Harbin Medical University, Harbin, 150001, PR China; The Key Laboratory of Anesthesiology and Intensive Care Research of Heilongjiang Province, Harbin, 150001, PR China.
  • 5 The Key Laboratory of Anesthesiology and Intensive Care Research of Heilongjiang Province, Harbin, 150001, PR China; The Key Laboratory of Myocardial Ischemia Organization, Chinese Ministry of Education, Harbin, 150001, PR China; State Key Laboratory of Frigid Zone Cardiovascular Diseases, Harbin, 150001, PR China; Department of Anesthesiology, Harbin Medical University Cancer Hospital, Harbin, 150081, PR China.
  • 6 Department of Anesthesiology, First Affiliated Hospital of Harbin Medical University, 199 Dazhi Road, Harbin, 150001, PR China.
  • 7 Department of Anesthesiology, Fourth Affiliated Hospital of Harbin Medical University, 37 Yiyuan Road, Harbin, 150001, PR China.
  • 8 Department of Anesthesiology, Second Affiliated Hospital of Harbin Medical University, Harbin, 150001, PR China; The Key Laboratory of Anesthesiology and Intensive Care Research of Heilongjiang Province, Harbin, 150001, PR China. Electronic address: yueziyong@hrbmu.edu.cn.
PMID: 40156957 DOI: 10.1016/j.redox.2025.103614
Abstract

Macrophages play a critical role in the development of sepsis-induced acute lung injury (si-ALI), with extracellular vesicles (EVs) acting as crucial mediators. However, the effects and mechanisms of macrophage-derived EVs on si-ALI remain unclear. This study demonstrated that macrophage-derived EVs induce endothelial Ferroptosis and barrier disruption during sepsis. Through proteomic Sequencing and reanalysis of transcriptomic and single-cell Sequencing data, guanylate-binding protein 2 (GBP2) was identified as a key EV molecule. Elevated GBP2 expression was observed in EVs and monocytes from the peripheral blood of sepsis patients, in LPS-stimulated THP-1 and RAW264.7 cells and their secreted EVs, and in macrophages within the lungs of CLP mice. Additionally, GBP2 expression in EVs showed a positive correlation with vascular barrier injury biomarkers, including ANGPT2, Syndecan-1, and sTM. Modulating GBP2 levels in macrophage-derived EVs affected EV-induced Ferroptosis in endothelial cells. The mechanism by which GBP2 binds directly to OTUD5 and promotes GPX4 ubiquitination was elucidated using RNA interference, adeno-associated virus transfection, and endothelial-specific Gpx4 knockout mice. A high-throughput screening of small-molecule compounds targeting GBP2 was conducted. Molecular docking, molecular dynamics simulations, and cellular thermal shift assays further confirmed that Plantainoside D (PD) has a potent binding affinity for GBP2. PD treatment inhibited the interaction between GBP2 and OTUD5, leading to a reduction in GPX4 ubiquitination. Further research revealed that PD treatment enhanced the pulmonary protective effects of GBP2 inhibition. In conclusion, this study explored the role of EV-mediated signaling between macrophages and pulmonary vascular endothelial cells in si-ALI, highlighting the GBP2-OTUD5-GPX4 axis as a driver of endothelial Ferroptosis and lung injury. Targeting this signaling axis presents a potential therapeutic strategy for si-ALI.

Keywords

Acute lung injury; Endothelial cells; Extracellular vesicles; Ferroptosis; Macrophage; Sepsis.

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