Retatrutide, a novel triple agonist targeting glucagon, GIP, and GLP-1 receptors simultaneously, achieved remarkable 31% body weight reduction in diet-induced obese mice with metabolic dysfunction-associated steatohepatitis (MASH). The compound significantly improved insulin resistance markers (HOMA-IR), reduced hepatic fat accumulation, and lowered triglycerides and cholesterol across both mouse and hamster models. Notably, hamsters showed altered food preferences, choosing healthier chow over high-fat diets. This represents a significant advancement in obesity pharmacotherapy. Current GLP-1 agonists like semaglutide typically achieve 15-20% weight loss in humans, making retatrutide's preclinical results potentially paradigm-shifting. The triple mechanism addresses multiple metabolic pathways simultaneously—glucagon for energy expenditure, GIP for insulin sensitivity, and GLP-1 for appetite suppression. However, the dramatic weight loss included both fat and lean muscle mass, raising questions about body composition preservation. The animal model limitations mean human translation remains uncertain, and the compound's safety profile needs thorough evaluation. If these results translate to humans, retatrutide could revolutionize treatment for severe obesity and MASH, conditions affecting millions worldwide with limited therapeutic options.