Abstract Body: Cardiometabolic syndrome has become a global health crisis, affecting nearly one in four adults in the U.S., with prevalence rising sharply with age from 7% in young adults to 45% in those over 60. As obesity and type 2 diabetes surge, over 40 million prescriptions for incretin-based therapies are written annually, underscoring their importance in metabolic disease management. Beyond glycemic control and weight loss, recent findings suggest these therapies may also protect the heart, yet the mechanisms remain unclear. Given the shared pathophysiology between metabolic disorders and cardiovascular diseases; chronic inflammation, oxidative stress, and endothelial dysfunction, understanding how incretin mimetics influence cardiac function is essential. This study aims to unveil the cellular mechanisms underlying the cardioprotective effects of incretin-based analogs in induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs), building on preliminary murine model data suggesting their role in modulating key signaling pathways involved in cardiomyocyte survival. We utilized iPSCs derived from two healthy Caucasian donors, without gender specificity, differentiated, replated, and matured a fraction into cardiomyocytes. We compared immature and mature cardiomyocytes using immunofluorescence staining to assess sarcomere fiber organization and mitochondrial density, along with contractile assays to evaluate functional properties. Mature iPSC-CMs were exposed to Tirzepatide, a dual GLP-1/GIP receptor agonist, in combination with a “metabolic stress cocktail”, followed with a quantitative PCR analysis to assess molecular changes associated with cellular response. From the results, the mature iPSC-CMs exhibited similar cardiometabolic functionality as the murine model, particularly in their capacity for fatty acid uptake and ATP generation. This observation, alongside the upregulation of key metabolic genes, informed our selection of transcriptomic gene targets for iPSC-CMs, which were chosen to further investigate the molecular mechanisms underlying the observed cardiometabolic responses. Overall, the cardiac functionality was enhanced after the treatment of Tirzepatide; further proteomic assays are being performed to validate the study.