Endothelial CYB5R1 is a Coenzyme Q reductase that suppresses ferroptosis and atherosclerosis

Endothelial CYB5R1 is a Coenzyme Q reductase that suppresses ferroptosis and atherosclerosis | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Biological Sciences - Article Endothelial CYB5R1 is a Coenzyme Q reductase that suppresses ferroptosis and atherosclerosis Adam Straub, Robert Hall, Svetlana Samovich, Mate Katona, Shuai Yuan, and 13 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7603489/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted You are reading this latest preprint version Abstract Spatial-temporal coordination of oxidoreductase substrate specificity and turnover regulates redox-mediated signaling, shaping physiological and pathological outcomes. Here, we reveal novel actions of cytochrome b5 reductase 1 (CYB5R1) when localized to the outer mitochondrial membrane of endothelial cells. Specifically, CYB5R1 functions as a Coenzyme Q (CoQ)–dependent redox cycler, protecting against iron-dependent lipid oxidation or ferroptosis. CYB5R1 catalyzes CoQ redox cycling via electron transfer reactions that suppresses both lipid hydroperoxide accumulation and ferroptosis. CoQ-insufficiency or disruption of CYB5R1-CoQ coupling impairs these reactions, leading to elevated hydrogen peroxide production and initiating a ferroptotic cascade. Ferroptosis plays a pathogenic role in atherogenesis, and we report that both global and endothelial-specific CYB5R1 knockout significantly exacerbate plaque formation. Through a rational chemical library design and screening, we synthesized and tested CP50, a quinone–nitroalkene hybrid that upregulates CYB5R1, prevents glutathione peroxidase-4 (GPX4) degradation, limits lipid oxidation, confers potent anti-ferroptotic activity and in a murine model, profoundly inhibit atherogenesis. These findings a) establish CYB5R1 as a novel mitochondrial “redox rheostat” that governs endothelial ferroptotic susceptibility through substrate redox regulation and b) reveals a safe small molecule therapeutic strategy that can impact a broad range of diseases. Biological sciences/Physiology/Cardiovascular biology/Cardiovascular diseases/Vascular diseases/Atherosclerosis Biological sciences/Cell biology/Cell death Biological sciences/Chemical biology/Enzyme mechanisms Biological sciences/Chemical biology/Pharmacology CYB5R1 ferroptosis redox lipid oxidation CoQ endothelial cell atherosclerosis Full Text Additional Declarations Yes there is potential Competing Interest. A.C.S., F.J.S. and B.A.F. acknowledge an interest in Creegh Pharmaceuticals, Inc. A.C.S received research funds from Bayer Pharmaceuticals. Cite Share Download PDF Status: Under Review Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-7603489","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Biological Sciences - Article","associatedPublications":[],"authors":[{"id":515441174,"identity":"dcd8677e-fb4c-47b7-bc7d-08f176183e6f","order_by":0,"name":"Adam 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Through a rational chemical library design and screening, we synthesized and tested CP50, a quinone–nitroalkene hybrid that upregulates CYB5R1, prevents glutathione peroxidase-4 (GPX4) degradation, limits lipid oxidation, confers potent anti-ferroptotic activity and in a murine model, profoundly inhibit atherogenesis. 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