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Metabolic syndromes, characterized by dyslipidemia, obesity, and insulin resistance, are major risk factors for the development of cardiomyopathy and heart failure. The development of these diseases is significantly influenced by lipotoxicity, a vital pathological process driven by excessive lipid accumulation. It contributes directly to cardiomyocyte dysfunction and apoptosis, resulting in structural and functional cardiac decline.Here, we investigated the protective role of Pontin (Ruvbl1) against lipid-induced damage in cardiomyocytes and established a relevant in vivo model. To examine the effects of Pontin, we employed H9c2 cells and primary neonatal rat cardiomyocytes (NRCMs), where Pontin was introduced using an adenoviral vector. Lipotoxicity was simulated by exposing cells to palmitic acid, a saturated fatty acid, at varying concentrations (0, 125, 250, and 500 μM) for a 48-hour period. Lipid droplet dynamics were assessed using a 3D model.In H9c2 cardiomyoblasts, Pontin overexpression significantly enhanced cell viability following palmitic acid treatment, reduced lipid droplet formation, and protected against lipid-induced apoptosis. Consistent results were observed in NRCM, where Pontin overexpression significantly improved cell viability after 125 μM palmitic acid stimulation and protected against lipid-induced apoptosis.To further investigate the in vivo relevance, we generated transgenic mice with cardiomyocyte specific Pontin overexpression. The PontincTG mice were fed with a high-fat diet (HFD) for 16 weeks, starting at 10 weeks of age. This regimen successfully induced metabolic syndrome, characterized by increased body weight, modest blood pressure elevation, impaired glucose tolerance and elevated serum cholesterol levels. Initial observation using electron microscopy revealed significantly higher cardiac lipid droplet accumulation in HFD-fed mice compared to controls, confirming lipid accumulation at the ultrastructural level. Subsequent analyses are underway to evaluate cardiac structure and functions, lipid accumulation in the heart and apoptosis levels.Overall, this study demonstrates that Pontin (Ruvbl1) effectively mitigates lipotoxicity in cardiomyocytes by reducing lipid accumulation and preventing apoptosis in vitro. Importantly, we established a high-fat diet-induced metabolic syndrome model in transgenic mice, characterized by significant cardiac lipid accumulation, which provides a robust platform for in vivo studies.