Epigallocatechin-3-gallate Restores X-irradiation-Induced Impairments in Cognitive Function and Hippocampal Neurogenesis by Suppressing the TLR4-NOX3/4 and ROS-NF-κB Pathways in Microglia

Abstract

X-irradiation, commonly used to ablate tumor cells, disrupts hippocampal neurogenesis and neurobehavioral function. However, strategies to restore X-irradiation-induced impairments in hippocampal neurogenesis and cognitive function are not well established. Epigallocatechin-3-gallate (EGCG) is recognized as a neuroprotective agent in neurological disorders, but its effects on X-irradiation-induced impairments in hippocampal neurogenesis and memory function remain unclear. In this study, X-irradiation impaired adult hippocampal neurogenesis by suppressing neural stem cell (NSC) proliferation, survival, and differentiation, and it decreased cognitive function by reducing synapse number and expression. EGCG treatment restored hippocampal neurogenesis by reducing TLR4–NOX3/4–ROS levels and inhibiting neuroinflammation via the TLR4–NF-κB pathway, leading to the suppression of proinflammatory cytokines. Furthermore, TLR4 shRNA transfection in BV2 cells followed by X-irradiation significantly reduced the expression of NOX3 and NOX4 and decreased ROS production. Similarly, EGCG treatment in X-irradiated BV2 cells reduced TLR4, NOX3, and NOX4 expression, decreased cytosolic Nrf2 levels while upregulating nuclear Nrf2 expression, and enhanced HO-1 expression, leading to a reduction in ROS production. These findings suggest that EGCG may be a promising therapeutic strategy to restore X-irradiation-induced damage in the central nervous system, promoting hippocampal neurogenesis, memory function, and synapse development. © The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2025.