Targeting macrophage ferritin heavy chain mitigates ferroptosis and lung injury in experimental acute respiratory distress syndrome.

Summary

This translational study reports enrichment of ferritin subunits (FTH1/FTL) in serum, monocytes, and alveolar macrophages from ARDS patients, validated in a murine hyperoxia lung injury model, and shows that targeting myeloid FTH1 reduces ferroptosis and lung injury. The mechanism links extracellular ferritin, macrophage iron handling, ferroptotic cell death, and inflammation, identifying FTH1 as a potential therapeutic target.

Key Findings

• FTH1 and FTL are enriched in serum, peripheral monocytes, and alveolar macrophages of ARDS patients and replicated in a murine hyperoxia model.
• Myeloid-specific deletion or inhibition of Fth1 reduced ferroptosis markers and attenuated lung injury in experimental models.
• Extracellular ferritin correlates with worsened outcomes, linking macrophage iron handling to inflammatory lung injury and suggesting FTH1 as a targetable mediator.

Clinical Implications

Identifies FTH1/ferritin axis as a potential target for interventions to reduce ferroptosis-driven lung injury in ARDS; supports development of FTH1-modulating therapies or iron/ferroptosis-directed treatments and biomarker studies of serum ferritin compartments in ARDS patients.

Limitations

• Translational gap: therapeutic modulation of FTH1 in humans and safety of targeting macrophage iron handling remain untested.
• Extent of clinical sample size and heterogeneity not specified in abstract; degree to which circulating ferritin subfractions predict outcomes requires larger cohorts.

Future Directions

Develop and test FTH1-modulating agents or ferroptosis inhibitors in preclinical ARDS models, validate serum/extracellular ferritin subfractions as prognostic biomarkers in large ARDS cohorts, and assess safety of targeting macrophage iron handling in translational trials.