BACKGROUND: Alzheimer's disease (AD) is a progressive neurodegenerative disorder with limited treatments. Schisandra total lignans (STL), the primary active component of Schisandra chinensis, shows potential in alleviating AD-related symptoms, though the mechanisms remain unclear. PURPOSE: Considering the promoting effect of neuronal ferroptosis on AD and the neuroprotective activity of STL, this study aimed to investigate the impact of STL on AD neuronal ferroptosis and elucidate its underlying mechanisms. METHODS: This study used 3xTg-AD mice and SH-SY5Y cells overexpressing APPswe as models. UHPLC/Q-TOF-MS was applied for identifying components in STL extract and the plasma of 3xTg-AD mice, as well as to detect cellular endogenous metabolites for one-carbon metabolism analysis. Behavioral tests, including the Y maze, novel object recognition, Morris water maze, and open field, were conducted to assess the cognitive function and emotional state. Histopathological examinations were performed using immunofluorescence, immunohistochemistry, Nissl staining, and transmission electron microscopy. The GSH, GSSG, NAD(H), NADP(H), and MDA levels, as well as GPX and GR activity were measured using assay kits. ROS, Fe RESULTS: Behavioral tests indicated that STL alleviated cognitive impairments and anxiety in 3xTg-AD mice. Histological analysis showed that STL decreased hippocampal Aβ levels, inhibited hippocampal neuronal ferroptosis, and mitigated synaptic damage. Cellular assays demonstrated that STL alleviated APPswe overexpression-induced ferroptosis and synaptic damage by activating the NADK/NADPH/GSH pathway, with NADK knockdown abolishing this neuroprotective effect of STL. Computational analysis and cellular thermal shift assay identified Gomisin D as the key STL component with strong affinity for NADK, driving its neuroprotective effects. CONCLUSION: NADK emerges as a novel potential therapeutic target for AD, with STL activating NADK, promoting NADPH and GSH production, thereby mitigating neuronal ferroptosis in AD.