Indoleamine 2,3-dioxygenase 1 drives epithelial cells ferroptosis in influenza-induced acute lung injury.
Summary
Influenza A virus drives ferroptotic death predominantly in airway and alveolar epithelium. Genetic and pharmacologic suppression of IDO1 mitigated ferroptosis, oxidative stress, and lung injury, positioning IDO1 as a tractable therapeutic target in viral ALI.
Key Findings
- Influenza A virus induces predominant ferroptosis in alveolar and bronchial epithelial cells.
- Ferrostatin-1 improved survival, weight loss, and lung injury in IAV-infected mice.
- IDO1 knockdown reduced ferroptosis-related oxidative/nitrative stress; pharmacologic IDO1 inhibition (1-methyl-tryptophan) improved ALI phenotype.
- Targeted lipidomics identified phospholipid peroxidation as a key mechanism.
Clinical Implications
Suggests evaluating IDO1 inhibitors and ferroptosis-modulating agents as adjuncts in severe viral pneumonia/ALI; biomarkers of lipid peroxidation could aid stratification.
Why It Matters
Reveals a druggable regulator (IDO1) of ferroptosis in viral ALI and provides multi-omics and intervention evidence supporting translational targeting.
Limitations
- Preclinical models may not reflect human ALI complexity; dosing and safety of IDO1 inhibitors in ARDS are untested.
- Cell type–specific contributions beyond epithelium (e.g., immune cells) require further study.
Future Directions
Test clinically relevant IDO1 inhibitors and ferroptosis modulators in diverse viral and non-viral ALI models, and develop biomarkers to select ferroptosis-high patients.
Study Information
- Study Type
- Case-control
- Research Domain
- Pathophysiology
- Evidence Level
- V - Mechanistic preclinical study with genetic and pharmacologic interventions in animal models.
- Study Design
- OTHER