{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,24]],"date-time":"2026-10-24T15:35:43Z","timestamp":1792856143042,"version":"4.5.0"},"reference-count":36,"publisher":"Oxford University Press (OUP)","license":[{"start":{"date-parts":[[2026,6,2]],"date-time":"2026-06-02T00:00:00Z","timestamp":1780358400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000780","name":"European Union","doi-asserted-by":"publisher","award":["101095413"],"award-info":[{"award-number":["101095413"]}],"id":[{"id":"10.13039\/501100000780","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100020655","name":"European Health and Digital Executive Agency","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100020655","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004359","name":"Swedish Research Council","doi-asserted-by":"publisher","award":["2023-02652"],"award-info":[{"award-number":["2023-02652"]}],"id":[{"id":"10.13039\/501100004359","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Heart-Lung Foundation","award":["20240697"],"award-info":[{"award-number":["20240697"]}]},{"name":"Region Stockholm","award":["RS2023-0859"],"award-info":[{"award-number":["RS2023-0859"]}]},{"name":"Sch\u00f6rling Foundation"},{"name":"China Scholarship Council and Foundations"},{"DOI":"10.13039\/501100004047","name":"Karolinska Institutet","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100004047","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Nanna Svartz Fond"},{"name":"Scientific Research","award":["1S33720N"],"award-info":[{"award-number":["1S33720N"]}]},{"name":"Research Council of the University of Antwerp"},{"name":"Swedish CArdioPulmonary bioImage Study"},{"DOI":"10.13039\/501100003793","name":"Swedish Heart-Lung Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100003793","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004063","name":"Knut and Alice Wallenberg Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100004063","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Swedish Research Council and VINNOVA"},{"name":"University of Gothenburg and Sahlgrenska University Hospital"},{"name":"Karolinska Institutet and Stockholm County Council"},{"name":"Link\u00f6ping University and University Hospital"},{"name":"Lund University and Sk\u00e5ne University Hospital"},{"name":"Ume\u00e5 University and University Hospital"},{"name":"Uppsala University and University Hospital"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background and Aims<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>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\u2013ACSL4 axis. In vivo, doxorubicin-induced valvular ferroptosis exacerbated valvular thickening in apoE\u2212\/\u2212 mice through ALOX5\u2013ACSL4 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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>These findings establish the ALOX5\u2013ACSL4 axis as a critical mediator of ferroptosis in CAVD and promising repurposing target for clinical intervention.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1093\/eurheartj\/ehag397","type":"journal-article","created":{"date-parts":[[2026,5,19]],"date-time":"2026-05-19T11:34:27Z","timestamp":1779190467000},"source":"Crossref","is-referenced-by-count":4,"title":["Ferroptosis promotes aortic stenosis through 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