Fibroblast growth factor 21 (FGF21) is an endocrine hormone predominantly expressed in the liver, with notable expression also observed in adipose tissue, pancreas, and skeletal muscle, where its transcription is markedly induced by metabolic stresses such as fasting and ketogenic diets, primarily under the control of PPARα and circadian rhythm regulators ^[1]. This protein plays a central role in systemic energy homeostasis by modulating glucose and lipid metabolism, enhancing insulin sensitivity, promoting hepatic fatty acid oxidation and ketogenesis, and stimulating glucose uptake in adipocytes through its actions on target tissues including the liver, adipose tissue, brain, and skeletal muscle ^[1-2]. Perturbations in FGF21 levels are implicated in a spectrum of metabolic disorders, including obesity, type 2 diabetes, non-alcoholic fatty liver disease (NAFLD), and cardiovascular disease, where elevated circulating levels often correlate with a state of FGF21 resistance, while diminished levels have been reported in conditions such as anorexia nervosa ^[3-4]. Furthermore, emerging research has highlighted a complex role for FGF21 in cancer, with studies suggesting its involvement in both tumor-promoting and tumor-suppressing activities depending on the cancer type and microenvironment ^[4]. huFGF21 mice are humanized models generated by replacing the sequence of the mouse Fgf21 gene in situ with the corresponding sequence from the human FGF21 gene. This model can be used to study the pathological mechanisms and therapeutic methods of metabolic diseases such as obesity, diabetes, and metabolic associated steatohepatitis (MASH), cardiovascular diseases, cancers, as well as the screening and development of FGF21-targeted drugs, and preclinical efficacy and safety evaluations.