What question did this study set out to answer?

This study aims to identify the role of the ALOX5-ACSL4 axis in ferroptosis related to aortic stenosis and explore its clinical applications.

June 4, 2026

Ferroptosis promotes aortic stenosis through 5-lipoxygenase.

Key Points

This study aims to identify the role of the ALOX5-ACSL4 axis in ferroptosis related to aortic stenosis and explore its clinical applications.
Integrated bulk and single-cell transcriptomics, immunohistochemistry, and primary human valvular interstitial cell models from 212 aortic valves.
Evaluated valvular ferroptosis and thickness in both doxorubicin-induced and wire injury models in mice.
Analyzed data from 4874 SCAPIS participants and 273550 UK Biobank individuals for aortic valve calcification and stenosis incidence.
Intra-leaflet hemorrhage correlated with calcification and ferroptosis biomarker presence in calcified valves.
Induction of ferroptosis in valvular interstitial cells caused lipid peroxidation and reduced viability, reversible by targeting ALOX5-ACSL4.
Inhibition of ALOX5 improved valve thickness and function in vivo, with arachidonic acid levels predicting calcification and stenosis incidence.

Abstract

BACKGROUND AND AIMS: Calcific aortic valve disease (CAVD) culminates in severe aortic stenosis, currently lacking pharmacological treatment. Intra-leaflet haemorrhage-induced iron overload promotes valvular ferroptosis. This study identifies a druggable ferroptosis pathway and validates its translational relevance across large-scale population cohorts. METHODS: Bulk- and single-cell transcriptomics, whole-mount histology, immunohistochemistry, and primary human valvular interstitial cell (VIC) models of 212 aortic valves from surgical patients were integrated for mechanistic insights. In vivo, valvular ferroptosis and thickness were assessed in a doxorubicin-induced ferroptosis mice model, and a wire injury model with ferroptosis inhibition was utilized to evaluate remodelling and haemodynamic obstruction. A total of 4874 participants of the Swedish CArdioPulmonary bioImage Study (SCAPIS) underwent cardiac computed tomography for aortic valve calcification determination and 273 550 individuals from the UK Biobank were followed for aortic stenosis incidence. RESULTS: Intra-leaflet haemorrhage was prevalent in calcified aortic valves and correlated positively with calcification and circulating ferroptosis biomarker. Bulk transcriptomics and single-cell RNA sequencing identified lipid peroxidation as the dominating valvular ferroptosis pathway centred on arachidonate 5-lipoxygenase (ALOX5). Inducing ferroptosis in VIC triggered lipid peroxidation and calcification while reducing viability, which were reversed by targeting the ALOX5-ACSL4 axis. In vivo, doxorubicin-induced valvular ferroptosis exacerbated valvular thickening in apoE-/- mice through ALOX5-ACSL4 upregulation. ALOX5 inhibition reduced valve thickness and haemodynamically improved valve function in the wire injury model. Arachidonic acid levels independently predicted aortic valve calcification and incident aortic stenosis in SCAPIS and UK Biobank, respectively, and positively correlated with circulating ferroptotic marker. CONCLUSIONS: These findings establish the ALOX5-ACSL4 axis as a critical mediator of ferroptosis in CAVD and promising repurposing target for clinical intervention.

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