Isoliquiritigenin, a Bioactive Blood Component Derived from Licorice, Activates Nrf2 Enzymes to Confer Protection Against Radiation-Induced Nerve Injury

Licorice is a traditional Chinese medicine; however, its bioactive constituents and specific molecular mechanisms responsible for protecting against radiation-induced brain injury remain poorly elucidated. Oxidative stress overactivation acts as the core pathological mechanism underlying radiation-triggered neuronal injury. This study aimed to investigate the neuroprotective effect and underlying mechanism of isoliquiritigenin (ISL), a major blood-absorbed component of licorice, against radiation-induced neural injury in C57BL/6J mice via the Keap1-Nrf2 signaling pathway. Molecular docking and MST analysis verified the strong binding affinity of ISL to Keap1. In vitro, ISL restored the viability of X-ray-irradiated PC12 cells; reduced LDH release and intracellular ROS accumulation; and enhanced SOD1 activity, GSH content, and T-AOC levels. Moreover, ISL upregulated the expression of antioxidant-related genes and induced Nrf2 nuclear translocation. In vivo, oral ISL administration ameliorated radiation-induced cognitive impairment, improved spatial learning and memory, alleviated hippocampal neuronal loss, and increased cerebral cortical Nrf2 expression in C57BL/6J mice. In conclusion, ISL alleviates radiation-induced neuronal injury by suppressing oxidative stress and activating the Keap1-Nrf2 signaling pathway, thus representing a promising therapeutic agent for the prevention and treatment of radiation brain injury.