Plasma-derived extracellular vesicles prime alveolar macrophages for autophagy and ferroptosis in sepsis-induced acute lung injury.

Summary

Septic plasma EVs carry miRNA/protein cargo that correlates with disease severity and independently predicts septic ARDS, notably LCN2, miR-122-5p, and miR-223-3p. Mechanistically, miR-223-3p in EVs activates Hippo signaling via MEF2C targeting to induce autophagy and ferroptosis in alveolar macrophages; in vivo inhibition attenuated lung injury.

Key Findings

• EV panels (miR-122-5p, miR-125b-5p, miR-223-3p, OLFM4, LCN2) associate with sepsis severity/prognosis with promising AUCs.
• LCN2, miR-122-5p, and miR-223-3p are independent predictors of septic ARDS.
• EV miR-223-3p activates Hippo signaling by targeting MEF2C, inducing autophagy and ferroptosis in alveolar macrophages; in vivo inhibition mitigates lung injury.

Clinical Implications

EV-derived miR-223-3p, miR-122-5p, and LCN2 could inform risk stratification for septic ARDS, while miR-223-3p inhibition or modulation of Hippo signaling in alveolar macrophages represents a potential therapeutic strategy.

Limitations

• Sample size and external validation cohorts are not specified in the abstract.
• Therapeutic targeting of EV pathways is preclinical; clinical efficacy remains untested.

Future Directions

Validate EV biomarker panels and thresholds in multicenter sepsis cohorts; develop miR-223-3p/Hippo-targeted interventions and delivery systems for ARDS.