Saponins from <i>Astragalus membranaceus</i> (Fisch.) Bge Alleviated Neuronal Ferroptosis in Alzheimer’s Disease by Regulating the NOX4/Nrf2 Signaling Pathway

Alzheimer's disease (AD) is a chronic neurodegenerative disease of the central nervous system caused by loss of neuronal or myelin function, accompanied by ferroptosis. <i>Astragalus membranaceus</i> (Fisch.) Bge. (<i>A. membranaceus</i>) is one of China's homologous lists of medicines and food, and its active component saponins have neuroprotective effects. This study examines the mechanism of saponins from <i>A. membranaceus</i> (AS) in treating AD. UPLC-Q-TOF-MS analyzed the composition of AS. Ferroptosis models were established to evaluate the anti-AD efficacy. As a result, AS treatment inhibited ferroptosis in SAMP8 mice by restoring iron homeostasis and lipid peroxidation (LPO) balance in the brain, thereby improving cognitive impairment and pathological damage. Mechanistically, AS treatment reduced Fe²⁺, MDA, and ROS levels and enhanced protein levels of SLC7A11, GPX4, FTH1, and FPN1. NADPH oxidase 4 (NOX4) overexpression revealed that AS treatment inhibited NOX4, thereby reducing NOX4 stability and regulating the NOX4/Nrf2 pathway in erastin-injured HT22 cells and significantly alleviating ferroptosis. Therefore, AS inhibited ferroptosis and improved AD by rebuilding iron homeostasis and LPO balance in the brain. AS has the potential to be a promising candidate medicine for AD.