WITHDRAWN: IMNRs Confer Selective Radioprotection of Normal Liver Tissue by Dual-Action Inhibition of Ferroptosis through Lipid Peroxide Detoxification and Mitochondrial Targeting

Ionizing radiation, from both environmental exposure and radiotherapy, induces severe tissue damage primarily through oxidative stress and lipid peroxidation. The liver is highly vulnerable, and a key unmet need is the development of agents that protect normal tissues without compromising therapeutic efficacy by selectively targeting these redox-sensitive pathways. However, its efficacy and the mechanism of selective radioprotection in the liver remain inadequately explored. This study systematically investigated the protective effect of IMNRs against radiation-induced liver injury, with a focus on its dual-action inhibition of ferroptosis and its differential impact on normal versus neoplastic hepatocytes. The results indicated that pretreatment with IMNRs significantly increased the survival rate of irradiated L-02 cells and effectively alleviated radiation-induced liver function damage (elevated ALT and AST) in mice. Molecular docking revealed that IMNRs could neutralize the toxic metabolite 4-HNE and target mitochondrial Complex III, reducing ROS generation at its source. IMNRs activated the Nrf2 signaling axis (upregulating HO-1 and GPX4), synergistically enhancing cellular antioxidant capacity, and protected mitochondrial function. They effectively stabilized the mitochondrial membrane potential (ΔΨ m ) in L-02 cells and prevented damage to mitochondrial cristae structures. IMNRs reversed metabolic disorders, significantly counteracting radiation-induced glutathione depletion and lipid peroxidation. Crucially, IMNRs exhibited entirely different effects on Huh-7 hepatoma cells: they neither rescued the post-irradiation clonogenic deficit nor reversed mitochondrial dysfunction and ultrastructural damage, thereby completely preserving the antitumor efficacy of radiotherapy. IMNRs thus cooperatively inhibits radiation-induced ferroptosis via multiple targets, protecting normal liver without compromising antitumor outcomes. This "differential radioprotection" highlights its clinical potential. • A novel imidazole nitroxide radical (IMNRs) is identified as a potent radioprotector. • IMNRs confer selective protection on normal hepatocytes but not hepatocellular carcinoma cells. • A dual-action mechanism involving mitochondrial targeting and direct 4-HNE neutralization is revealed. • The protection is achieved through multi-level inhibition of radiation-induced ferroptosis. • Nrf2 pathway activation and metabolic reprogramming are pivotal in the protective process.