Abstract Body: Diagnoses of prediabetes and metabolic syndromes, such as metabolic-associated steatotic liver disease, are increasing at an alarming rate worldwide, often simultaneously. A significant consequence of these is high risk of cardiovascular disease, highlighting the need for cardiac-specific therapeutics for intervention during the prediabetic stage. Recent studies have demonstrated that chemogenetic activation of the cardiac parasympathetic system through hypothalamic oxytocin (OXT) neurons provides cardioprotective effects in heart disease models by targeting excitatory neurotransmission to brainstem cardiac vagal neurons. In a prediabetic rat model, we hypothesized that stimulating this neural network would offer cardioprotection. To test this, we induced prediabetes through prolonged high-fat, high-fructose feeding. We stereotactically injected viral vectors into the paraventricular nucleus (PVN) of the hypothalamus in neonatal rats to express designer receptors exclusively activated by designer drugs (DREADDs) in a subset of PVN OXT neurons, and chronically activated them using the designer drug clozapine-n-oxide (CNO). Treated animals exhibited improved cardiac diastolic function and reduced left ventricular fibrosis compared to non-treated diseased animals after 4 weeks of CNO, with no change to systemic insulin resistance, hyperinsulinemia, and elevated triglycerides. Transcriptional analysis of left ventricular tissue indicates the preservation of pathways involved in metabolism (Pdk4, Pdp1, Hk2) and ion handling (Sln, Atp1a2, Atp1a4) in treated compared to diseased animals. These findings underscore the benefits of stimulating the OXT network to counteract prediabetic cardiomyopathy, independent of systemic prediabetes. OXT neurons and their downstream networks appear to be a promising therapeutic target for activating protective parasympathetic-mediated cellular pathways within the heart during prediabetic cardiomyopathy.