Alzheimer's disease (AD) is a complex neurodegenerative disorder, and current therapies mainly offer symptomatic relief. Given that the pathophysiology of AD is multifaceted, a multimodal therapeutic strategy targeting multiple molecular pathways implicated in AD-related pathogenesis represents a pragmatic avenue for impeding the advancement of AD. In this study, we evaluated the anti-Alzheimer effects of an HDAC6 inhibitor WY118, both alone and in combination with lithium chloride (LiCl), a GSK-3β inhibitor, to synergistically suppress ferroptosis. The combination of compound WY118 and LiCl demonstrated significant synergistic effects in both cellular models of AD induced by glutamate and streptozotocin. The findings suggest that compound WY118, in particular in combination with LiCl, exhibits potent anti-Alzheimer effects by synergistically suppressing ferroptosis. Studies on the mechanism of action indicated that the combination treatment significantly reduced tau phosphorylation and inhibited p38 MAPK signaling. This combination therapy holds promise for developing more effective treatments for AD.
