Ferroptosis promotes aortic stenosis through 5-lipoxygenase.

Summary

Integrating human valve omics, cell models, mouse experiments, and two population cohorts, this study identifies the ALOX5–ACSL4 lipid peroxidation axis as a central ferroptosis driver of calcific aortic valve disease. Pharmacological ALOX5 inhibition reduced valve thickening and improved hemodynamics in vivo, while arachidonic acid predicted valve calcification and incident aortic stenosis in SCAPIS and UK Biobank.

Key Findings

• ALOX5-centered lipid peroxidation is the dominant ferroptosis pathway in calcified human aortic valves.
• Targeting the ALOX5–ACSL4 axis reverses VIC lipid peroxidation/calcification and reduces valve thickening with hemodynamic improvement in vivo.
• Arachidonic acid independently predicts aortic valve calcification (SCAPIS) and incident aortic stenosis (UK Biobank) and correlates with circulating ferroptosis markers.

Clinical Implications

ALOX5 pathway inhibitors (e.g., 5-lipoxygenase-directed agents) merit evaluation as disease-modifying therapies for calcific aortic valve disease, with arachidonic acid and ferroptosis markers as potential companion diagnostics.

Limitations

• Causal inference in population analyses remains observational despite mechanistic support.
• Translational dosing, safety, and target engagement of ALOX5 inhibitors in humans are untested for valve disease.

Future Directions

Launch early-phase trials of ALOX5-pathway inhibitors with biomarker-guided enrichment; evaluate ferroptosis signatures as prognostic and pharmacodynamic markers in CAVD.