Metabolic Interplay in Acute Lung Injury: PARK7 Integrates FADS1/2-Dependent PUFA Metabolism and H3K14 Lactylation to Attenuate Endothelial Ferroptosis and Dysfunction.

Summary

Multi-omics and in vivo experiments reveal that downregulated PUFA synthesis in pulmonary endothelium drives ferroptosis in ALI, while restoring FADS1/2 activity or supplementing omega-3 PUFAs preserves barrier function and ameliorates injury. PARK7, via BMP–SMAD signaling and H3K14 lactylation, reinstates FADS1/2 and counters ferroptosis, defining a targetable metabolic–epigenetic axis.

Key Findings

• PUFA synthesis pathways, especially omega-3, are downregulated in pulmonary endothelial cells during LPS-induced ALI.
• Restoring FADS1/2 activity or supplementing omega-3 fatty acids protects against endothelial ferroptosis and restores barrier function.
• Endothelial cell–specific FADS1/2 overexpression and whole-lung FADS1/2 overexpression plus ALA supplementation ameliorate ALI in vivo.
• PARK7 regulates FADS1/2 via BMP–BMPR–SMAD1/5/9 signaling; H3K14 lactylation drives a protective feedback loop countering ferroptosis.

Clinical Implications

Suggests testable interventions (dietary omega-3s, FADS1/2 upregulation, PARK7/BMP pathway modulation) to mitigate endothelial dysfunction and ferroptosis in ARDS; potential biomarkers include FADS1/2 expression and histone lactylation status.

Limitations

• Preclinical models (LPS-induced ALI) without human clinical validation
• Potential pathway specificity and off-target effects not fully addressed

Future Directions

Validate the PARK7–BMP–FADS1/2 axis in human ARDS samples; test omega-3 supplementation and pathway modulators in translational models and early-phase trials.