Blocking the prostaglandin-degrading enzyme 15-PGDH completely prevented muscle mass loss during semaglutide treatment in obese mice, while maintaining the drug's weight loss benefits. The 15-PGDH inhibitor enhanced muscle stem cell function and myofiber growth, leading to improved strength recovery after injury. This finding addresses one of the most concerning side effects emerging from the widespread adoption of GLP-1 receptor agonists like Ozempic and Wegovy. Current evidence suggests that 25-40% of weight lost on these medications comes from lean muscle mass rather than fat, raising concerns about long-term metabolic health and functional capacity. The identification of 15-PGDH as a therapeutic target is particularly compelling because this enzyme naturally increases with aging and injury, making it a logical intervention point for preserving muscle during weight loss. While promising, this mouse study requires human validation before clinical application. The prostaglandin pathway's role in inflammation and cardiovascular health also necessitates careful safety evaluation. If translatable to humans, 15-PGDH inhibition could represent a paradigm shift in obesity treatment, allowing patients to achieve weight loss benefits while preserving the muscle mass critical for metabolic health and physical function.