Upon the induction of ischemia, we observed a poorer outcome of FGF21 deficiency in the experimental tMCAO mouse model with enlarged brain infarction and exacerbated degeneration of long-term sensorimotor performance, suggesting that FGF21 acts as a neuroprotective regulator in the control of neural injury after ischemia; this result is supported by the RNA sequencing data showing that the expression of neuronal function-associated genes in astrocytes after tMCAO was decreased by FGF21 knockdown. Here, FGF21 is linked to ischemia.