ArticleResearch square2025
Endothelial CYB5R1 is a Coenzyme Q reductase that suppresses ferroptosis and atherosclerosis.
Article in Research square, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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18 authors.
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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.
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