Exploring the effect of Kaixin San on Alzheimer's disease by regulating the Keap1/Nrf2/GPX4 signaling pathway to inhibit ferroptosis based on metabolomics and gut microbiota analysis.

Abstract

Alzheimer's disease (AD), as a common neurodegenerative disease, seriously affects the cognitive function and quality of life of patients, bringing a heavy burden to society and families. In recent years, traditional Chinese medicine (TCM) formula Kaixin San (KXS) has shown considerable potential in the treatment of AD. KXS can ameliorate cognitive dysfunction in AD model animals, but its action mechanism remains not fully elucidated. This study aims to further elucidate the action mechanism of KXS. To this end, we employed a variety of advanced technical methods, including neuropathological, molecular biological, metabolomic, and gut microbiota analysis techniques, to conduct systematic multi-dimensional research. The results demonstrated that KXS can significantly improve the learning and memory abilities of AD rats, alleviate hippocampal neuronal damage, reduce β-amyloid (Aβ) expression, and activate antioxidant activity by targeting the Keap1/Nrf2/GPX4 signaling pathway, thereby inhibiting ferroptosis. Metabolomic analysis reveals that KXS exerts a regulatory effect on metabolites, while gut microbiota analysis shows that KXS significantly promotes the proliferation of beneficial bacteria and reduces the abundance of pathogenic bacteria, thereby regulating gut microbiota homeostasis, inhibiting excessive activation of neuroinflammation, and alleviating neuronal damage induced by inflammatory factors. Further correlation analysis reveals a strong correlation between metabolites and gut microbiota in AD rats. In addition, KXS inhibits ferroptosis and oxidative stress by activating the Keap1/Nrf2/GPX4 signaling pathway, and simultaneously regulates serum lipid metabolism-related pathways to maintain metabolic homeostasis and gut microbiota balance, thereby inhibiting excessive neuroinflammatory activation and alleviating neuronal damage.