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