Abstract
Chronic stress can lead to nervous system dysfunction and depression-like behaviors in animals. Gypenosides can improve chronic stress-induced neuronal damage, but the protective mechanism remains poorly understood. This study aims to investigate the effect and mechanism of gypenosides on chronic stress-induced neuronal ferroptosis. Therefore, we established a chronic stress-induced neuronal damage model in vitro using corticosterone to induce PC12 cell injury. We demonstrated that ferroptosis inhibitors DFO and Ferrostatin-1 alleviated corticosterone-induced cell death in PC12 cells by reducing iron accumulation, lipid peroxidation, and increasing cell viability. Meanwhile, gypenosides attenuated ferroptosis agonist Erastin-induced ferroptosis in PC12 cells. Then, gypenosides ameliorated corticosterone-induced ferroptosis in PC12 cells. In terms of molecular mechanisms, gypenosides decreased the expression of Hepcidin and DMT1, and increased the expression of Ferritin and FPN1, thereby improving corticosterone-induced iron homeostasis disorders and iron accumulation. Moreover, gypenosides improved corticosterone-induced lipid peroxidation by inhibiting GLS2 expression, upregulating the expression of SLC7A11 and glutathione peroxidase 4, and reducing glutamate accumulation and GSH depletion. Gypenosides also reduced corticosterone-induced release of inflammatory cytokines, the expression of TNFR1, and the phosphorylation of NF-κB and p53 in PC12 cells. These findings indicate that gypenosides attenuate corticosterone-induced ferroptosis by inhibiting TNF-α/NF-κB signaling pathway in PC12 cells.