Extracellular vesicle-packaged GBP2 from macrophages aggravates sepsis-induced acute lung injury by promoting ferroptosis in pulmonary vascular endothelial cells.
- Design
- Design 9 of 10
- Novelty
- Novelty 9 of 10
- Journal
- Journal 8 of 10
- Clinical
- Clinical 8 of 10
Summary
Macrophage EVs carrying GBP2 trigger endothelial ferroptosis via direct binding to OTUD5 and promotion of GPX4 ubiquitination, disrupting the vascular barrier in sepsis-induced lung injury. Plantainoside D binds GBP2, disrupts the GBP2–OTUD5 interaction, reduces GPX4 ubiquitination, and mitigates lung injury in preclinical models.
Key Findings
- Macrophage-derived EVs induce endothelial ferroptosis and barrier disruption in sepsis models.
- GBP2 is enriched in EVs and binds OTUD5 to promote GPX4 ubiquitination, driving ferroptosis.
- Plantainoside D binds GBP2, disrupts GBP2–OTUD5 interaction, reduces GPX4 ubiquitination, and attenuates lung injury.
Clinical Implications
Suggests GBP2 or the OTUD5–GPX4 ubiquitination checkpoint as therapeutic targets for sepsis-induced lung injury; EV-GBP2 may serve as a biomarker of endothelial injury. Translation requires safety/pharmacokinetic studies and early-phase clinical trials.
Why It Matters
Identifies a previously unrecognized EV-mediated GBP2–OTUD5–GPX4 axis that drives endothelial ferroptosis in sepsis, with a small molecule that pharmacologically targets the pathway.
Limitations
- Preclinical only; no interventional human data to establish clinical efficacy
- EV-GBP2 quantitation and small-molecule PD require pharmacokinetic/toxicity profiling and off-target assessment
Future Directions
Validate EV-GBP2 as a biomarker in prospective sepsis cohorts and advance GBP2-targeting agents (e.g., PD) through pharmacology and early-phase clinical testing.
Study Information
- Study Type
- Case-control
- Research Domain
- Pathophysiology
- Evidence Level
- V - Preclinical mechanistic study in cells and mice without human intervention.
- Study Design
- OTHER