This proposal will investigate the role of the selenium (Se)-recycling enzyme, selenocysteine lyase (Scly), in combination with high fructose and dietary Se deficiency impacts cardiac function. Se deficiency has been associated with an increased risk of cardiometabolic disorders including type 2 diabetes (T2D) and atherosclerosis. A driver of cardiometabolic disorders such as T2D in humans is the overconsumption of fructose. High dietary fructose has been shown to induce insulin resistance, oxidative stress and cardiac lipid species such as triacylglycerols and diacylglycerols that are associated with cardiovascular diseases (CVDs), In most tissues, Se maintains redox homeostasis by controlling the levels of selenoproteins, such as glutathione peroxidases 1 and 4 (GPX1 and GPX4) and thioredoxin reductases 1 and 2 (TXNRD1 and TXNRD2), that curb reactive oxygen species (ROS), and in the case of GPX4, regulates ferroptosis. However, it is unknown if Scly modulates Se and selenoprotein levels in the heart, especially upon exposure to a high- fructose diet. In Se-dependent tissues such as the liver, especiallywhen Se is limiting, selenoprotein degradation may become a source of Se for selenoproteins, i.e. Se recycling, a reaction carried out by the enzyme selenocysteine lyase (Scly). The experiments in this proposal will determine how the heart metabolizes and recycles Se, impacting selenoprotein levels and activity, and overall heart function in Se- deficient states combined with a high fructose diet. Aim 1 will determine if Se recycling is activated in the heart in response to a high fructose diet. Aim 2 will determine if Scly action reduces oxidative stress and ferroptosis in Se-deficient cardiomyocytes. The overall impact of this proposal is to understand how Se metabolism and recycling in the heart regulates local Se levels and modulates heart physiology in a high fructose environment. This will guide improvements on nutritional recommendations with Se supplementation or aid in the use of nanoparticle therapeutics to treat CVD.