Ferroptosis promotes aortic stenosis through 5-lipoxygenase

Area of Science:

• Cardiovascular Research
• Cellular Biology
• Biomarkers

Background:

• Calcific aortic valve disease (CAVD) leads to severe aortic stenosis, a condition lacking pharmacological treatments.
• Intra-leaflet hemorrhage and subsequent iron overload contribute to valvular ferroptosis in CAVD.
• This study investigates a druggable ferroptosis pathway implicated in CAVD.

Purpose of the Study:

• To identify and characterize a key ferroptosis pathway in calcific aortic valve disease.
• To validate the translational relevance of this pathway in large-scale population cohorts.
• To explore the ALOX5-ACSL4 axis as a potential therapeutic target for aortic stenosis.

Main Methods:

• Integrated analysis of bulk and single-cell transcriptomics, histology, and human valvular interstitial cell (VIC) models from 212 aortic valves.
• In vivo studies using doxorubicin-induced ferroptosis mouse models and wire injury models with ferroptosis inhibition.
• Analysis of cardiac computed tomography data from 4874 participants (SCAPIS) and incidence data from 273,550 individuals (UK Biobank).

Main Results:

• Prevalence of intra-leaflet hemorrhage in calcified valves correlated with calcification and ferroptosis biomarkers.
• Lipid peroxidation via the ALOX5-ACSL4 axis was identified as the central ferroptosis pathway in VICs.
• ALOX5 inhibition in vivo reduced valvular thickening and improved hemodynamics; arachidonic acid levels predicted aortic valve calcification and stenosis incidence.

Conclusions:

• The ALOX5-ACSL4 axis is a critical mediator of ferroptosis in calcific aortic valve disease.
• Targeting the ALOX5-ACSL4 axis represents a promising therapeutic strategy for aortic stenosis.
• Findings support the repurposing of existing drugs or development of new interventions targeting this pathway.