This presentation showcases the effectiveness of an inhibitor targeting equilibrative nucleoside transporter (ENT)-1 for addressing both Alzheimer's disease (AD) and the associated sleep disturbances. Our findings demonstrate that the ENT1 inhibitor effectively countered the elevation of nitric oxide, caspase 3, and phosphorylated γ-H2AX. It also heightened the activity of nuclear DNA-dependent serine/threonine protein kinase (DNA-PKcs) through the non-homologous end joining (NHEJ) pathway, aiding in the mending of DNA double-strand breaks. This intervention mitigated the loss of cholinergic neurons in AD-afflicted mice. Notably, the ENT1 inhibitor ameliorated cognitive deficits observed in tasks like the Morris Water Maze (MWM) and Novel Object Recognition (NOR). Moreover, our investigation revealed that the ENT1 inhibitor not only relieved sleep disruptions induced by AD but also displayed efficacy in managing stress-induced insomnia. Given the intertwined nature of sleep disruption and AD progression, our results underscore the potential of this innovative ENT1 inhibitor as a prospective treatment for Alzheimer's disease.