Abstract
Excessive stress is a well-established contributor to neurological damage, insomnia, and depression, imposing a significant burden on individuals and society. This underscores the urgent need for effective stress-relief strategies. The main purpose of this study was to explore the protective effects of Polygala tenuifolia (PT) and its bioactive compound, tenuifolin, against corticosterone-induced neurotoxicity, with a focus on ferroptosis, oxidative stress, and neuroinflammation. Both PT extracts and tenuifolin mitigated corticosterone-induced cellular damage. Tenuifolin reversed the corticosterone-induced dysregulation of ferroptosis-associated proteins, such as SLC7A11, GPX4, and Nrf2, leading to a marked reduction in ferroptosis levels. Molecular dynamics simulations revealed that corticosterone significantly altered the conformation and binding energy of the SLC7A11/SLC3A2 complex, critical for ferroptosis regulation. These changes were reversed by tenuifolin. Additionally, tenuifolin alleviated corticosterone-induced oxidative stress and neuroinflammation, both of which accelerated ferroptosis. In conclusion, these results indicate that tenuifolin attenuates corticosterone-induced neurotoxicity by modulating ferroptosis, oxidative stress, and neuroinflammation. This study provides a theoretical foundation for the application of PT and tenuifolin in stress-induced nerve damage.