In conclusion, the current study has revealed the promising neurotherapeutic potential of Lira against 3-NP-induced HD via modulating the crosstalk between cAMP/CREB/BDNF/TrkB, PI3K/Akt/GSK-3β/β-catenin, and GSK-3β/CREB trajectories. This evidence concerns the gene CREB1 and Huntington disease.