FGF21 is a stress-responsive endocrine hormone that regulates systemic metabolic homeostasis through the FGFR1/β-klotho receptor complex 1. Functionally, FGF21 stimulates glucose uptake in adipocytes via GLUT1 induction and regulates insulin sensitivity and lipid homeostasis. Beyond metabolic control, FGF21 acts as a pleiotropic hormone with tissue-specific effects mediated through coordinated central nervous system and peripheral signaling. In the CNS, FGF21 signals glutamatergic neurons to increase hepatic sympathetic nerve activity, suppressing de novo lipogenesis and reducing hepatic triglycerides and fibrosis 2. Additionally, FGF21 directly targets hepatocytes to reduce cholesterol levels and acts on cardiomyocytes to enhance mitochondrial bioenergetics via the PI3K/AKT/PDK4 axis 3. FGF21 demonstrates broad therapeutic potential across multiple diseases: it ameliorates metabolic dysfunction-associated steatohepatitis (MASH) 2, improves heart failure with preserved ejection fraction 3, mitigates liver injury during sepsis through autophagy-mediated suppression of proinflammatory macrophages 4, exerts antifibrotic effects in pulmonary fibrosis by inhibiting alveolar epithelial cell apoptosis 5, and protects against ventilator-induced lung injury by suppressing NLRP3-mediated pyroptosis 6. However, native FGF21's poor pharmacokinetic properties necessitate development of long-acting analogs for clinical translation 1.