NRF2/miR-17-5p/TMEM16F axis regulates the crosstalk of inflammation and thrombosis in sepsis.

Summary

Using patient samples, LPS-induced mouse models, and endothelial cell assays, the authors identify an NRF2/miR-17-5p/TMEM16F regulatory axis that drives both inflammation and microvascular thrombosis in sepsis. Genetic or molecular interruption of this axis reduced mortality, inflammation, thrombosis, and organ injury, and patient plasma levels of TMEM16F/miR-17-5p correlated with DIC and inflammation.

Key Findings

• TMEM16F is upregulated in sepsis models; its deletion reduces mortality, inflammation, and microthrombi in LPS-induced septic mice.
• NRF2 promotes TMEM16F transcription and suppresses miR-17-5p, thereby increasing TMEM16F in endothelial cells; inhibiting miR-17-5p reverses NRF2-silencing effects.
• Plasma TMEM16F and miR-17-5p levels correlate with coagulation activation, inflammation, and DIC scores in septic patients.

Clinical Implications

TMEM16F and miR-17-5p could serve as biomarkers for coagulopathy risk stratification (e.g., DIC) and as targets for anti-thromboinflammatory therapies in sepsis. Modulating NRF2/miR-17-5p/TMEM16F may attenuate immunothrombosis and organ injury.

Limitations

• Preclinical LPS model may not capture all clinical sepsis phenotypes
• Sample size and patient cohort characteristics are not detailed in the abstract

Future Directions

Evaluate therapeutic modulation of the NRF2/miR-17-5p/TMEM16F axis in clinically relevant sepsis models and early-phase trials; develop assays for TMEM16F/miR-17-5p monitoring in DIC risk stratification.