B6-hFGF21 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.