Discovery of Lignans and Stilbenes from the Seeds of Astragalus complanatus in Ferroptosis Regulation via Directly Acting on SLC7A11/GPX4 Pathway

The seeds of Astragalus complanatus (SAC), a medicinal food homologous resource with health benefits and agroeconomic value, remain underexplored regarding their bioactives. In this work, a phytochemical investigation led to the isolation of 26 secondary metabolites, including eight new neolignans, astraligans A-H (4, 5, 8, 9, 12, 13a, 13b, and 14), and one new stilbene, acetylpiceid (22), along with 17 known compounds. Their structures were elucidated using spectroscopic data analyses and quantum chemistry calculations. In RSL3-stimulated HT22 cells, (+)-pinoresinol (0.25-10 μM) and desoxyrhapontigenin (2.5-20 μM) dose-dependently enhanced cell viability and inhibited Ferroptosis via regulating the System Xc^--GSH-GPX4 axis and upregulating SLC7A11 mRNA. Network pharmacology, molecular docking, and dynamics simulations revealed AKR1C1 as a potential upstream target modulating Ferroptosis. This work provides a scientific basis for developing SAC into functional neuroprotective agents and supports its value-added utilization as an agricultural resource.