Saponins from Astragalus membranaceus (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. Astragalus membranaceus (Fisch.) Bge. (A. membranaceus) 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 A. membranaceus (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.