S100A9 modulates USP7-mediated stabilization of NCOA4 to promote ferroptosis in sepsis-associated acute lung injury.

Summary

This study uncovers a DAMP-driven S100A9–USP7–NCOA4 axis that stabilizes NCOA4 to sustain ferritinophagy and ferroptosis in alveolar macrophages during sepsis. Genetic disruption of S100A9 or pharmacologic inhibition of USP7 (P5091) mitigated ferroptosis and lung injury in CLP sepsis, and higher USP7/NCOA4 expression in patients correlated with worse 28-day survival.

Key Findings

• S100A9 recruits USP7 to NCOA4, enabling K63-linked deubiquitination at K42 and K181 and stabilizing NCOA4.
• Stabilized NCOA4 sustains ferritinophagy, iron release, lipid peroxidation, and ferroptosis in alveolar macrophages.
• S100A9 knockout or USP7 inhibition (P5091) suppresses ferroptosis and alleviates lung injury in CLP sepsis.
• USP7 and NCOA4 co-expression in sepsis patients correlates with reduced 28-day survival.

Clinical Implications

USP7 inhibition or targeting the S100A9–USP7 interface could emerge as therapeutic strategies for sepsis-associated acute lung injury; expression of USP7/NCOA4 may serve as risk biomarkers.

Limitations

• Preclinical murine model may not fully recapitulate human SALI heterogeneity
• Human data are correlative; specificity and safety of USP7 inhibition in sepsis need clinical evaluation

Future Directions

Develop selective USP7 inhibitors or disruptors of the S100A9–USP7 interface, validate efficacy and safety in large-animal models, and prospectively evaluate USP7/NCOA4 as biomarkers in sepsis cohorts.