Our findings unify the current understanding of FGF21’s metabolic roles and physiological targets, leveraging transformative insights into heart physiology, metabolic flux, and mitochondrial biology, which have profound strategic implications for (1) developing pharmacotherapies targeting cardiac diseases associated with mitochondrial and energy deficiencies, alongside MASH, hyperlipidemia, and obesity,22,23 and (2) designing caloric restriction and physical training interventions to improve physical strength, fitness, aging, and longevity. This evidence concerns the gene FGF21 and Obesity.