FGF21 is a stress-responsive endocrine fibroblast growth factor that regulates systemic metabolic homeostasis through signaling via FGFR1 and β-klotho (KLB). It stimulates glucose uptake in adipocytes by inducing GLUT1 expression and plays a central role in inter-organ crosstalk affecting metabolism, immune function, and cardiovascular health. Although hepatic tissues are the primary source across species, FGF21 expression also occurs in adipose tissue, thymus, heart, pancreas, and skeletal muscle 1. FGF21 dysregulation is implicated in multiple disease states. Elevated circulating FGF21 levels associate with obesity, type 2 diabetes, cardiovascular disease, and metabolic dysfunction-associated steatohepatitis (MASH), where FGF21-based therapeutics show promise 23. Recent mechanistic studies reveal FGF21 reverses MASH through distinct pathways: CNS signaling reduces hepatic triglycerides and fibrosis via sympathetic activation, while direct hepatocyte signaling lowers cholesterol 4. In heart failure with preserved ejection fraction, FGF21 enhances cardiac mitochondrial function through adiponectin and PDK4 regulation 5. FGF21 also protects against pulmonary fibrosis by inhibiting alveolar epithelial apoptosis 6 and ameliorates septic liver injury by suppressing proinflammatory macrophages 7. Clinical translation faces challenges: native FGF21 has poor pharmacokinetics, and while FGF21 analogues and FGFR1-KLB agonistic antibodies have entered clinical trials in obesity and NASH, glycemic control endpoints were not met, though dyslipidemia and liver fibrosis markers improved substantially 2.