Quercetin Targets HSP90α and Regulates Keap1/Nrf2 Pathway to Inhibit Crosstalk between Apoptosis and Ferroptosis in Oxidatively Stressed Neurons

The rising incidence and mortality rates associated with Alzheimer's disease (AD) have garnered significant attention. The interplay between ferroptosis and apoptosis, both of which are driven by oxidative stress, contributes to neuronal death and accelerates the progression of AD. In this study, we observed that neuronal cells exhibited characteristics of both ferroptosis and apoptosis following exposure to a specific concentration of hydrogen peroxide; both processes could be effectively inhibited by quercetin. To further investigate the precise mechanisms, we conducted target enrichment analysis utilizing databases pertinent to quercetin, AD, oxidative stress, ferroptosis, and apoptosis. Our findings identified HSP90AA1 as a potential key target through which quercetin disrupts the interplay between ferroptosis and apoptosis. We subsequently focused on HSP90α, encoded by HSP90AA1, and validated its role in ferroptosis and apoptosis using HSP90α and Nrf2 inhibitors. Our results demonstrate that under oxidative stress conditions, quercetin induces the activation of HSP90α. This activated chaperone binds to kelch-like ECH-associated protein 1 (Keap1), which disrupts the Keap1-Nrf2 complex and facilitates the release of nuclear factor erythroid 2-related factor 2 (Nrf2). The liberated Nrf2 translocates to the nucleus, initiating the expression of cytoprotective genes. Once in the nucleus, Nrf2 activates the Glutathione peroxidase 4 (GPX4) pathway and the expression of B-cell lymphoma-2 (Bcl-2) family proteins to inhibit ferroptosis and apoptosis. This study elucidates the crosstalk mechanism by which quercetin modulates neuronal ferroptosis and apoptosis under oxidative stress, providing new insights and potential therapeutic targets for the prevention and treatment of AD.