Isorhamnetin Confers Radioprotection by Activating the Nrf2 Antioxidant Pathway and Restoring Metabolic Homeostasis

Ionizing radiation (IR) can induce excessive production of reactive oxygen species (ROS), triggers oxidative stress, ultimately causes cell death, tissue injury, and even tumor formation in organisms. Natural products intervention are an effective way to alleviate IR damage. Here the radioprotective effect and underlying mechanism of the dietary flavonoid isorhamnetin (ISO) were investigated by 60 Coγ-induced HL-7702 cells and mouse models. The results suggested that ISO could significantly inhibit IR-induced intracellular ROS accumulation and cell death in vitro . Then ISO intervention could effectively alleviate IR-induced liver damage, upregulate superoxide dismutase (SOD) and glutathione (GSH) levels, reduce malondialdehyde (MDA) production, and activate Nrf2/Keap1/HO-1 signaling pathway at the protein level. Furthermore, the serum untargeted metabolomics analysis revealed that ISO could markedly restored metabolic balance by regulating key polyunsaturated fatty acids, including docosahexaenoic acid (DHA) and alpha-linolenic acid (ALA). Collectively, these results demonstrated the promising radioprotective potential of ISO as a natural active component, which supported its future application in the research and development of functional foods.