Genistein Protects Against Lead-Induced Cognitive Impairment Through a Glutathione-Dependent Redox–Mitochondrial Apoptosis Axis

Lead exposure remains a pervasive environmental and public health threat, imposing a substantial burden of neurodevelopmental and cognitive dysfunction, yet safe mechanism-oriented interventions remain limited. Genistein, a soybean-derived isoflavone with antioxidant and neuroprotective potential, may counter heavy metal-induced neural injury; however, whether its efficacy is associated with redox–metabolic remodeling is unclear. Here, we evaluated genistein in lead-exposed C57BL/6J mice and lead-challenged HT22 hippocampal neurons. Genistein improved novel-arm exploration and spatial memory without altering locomotor or swimming performance, and attenuated neuronal disorganization and apoptosis in hippocampal CA1, CA3 and dentate gyrus regions. These protective effects were accompanied by reduced blood and hippocampal lead accumulation, restored glutathione redox balance, enhanced antioxidant capacity, preserved mitochondrial integrity, and suppressed Bax/Caspase-3-associated apoptotic signaling. Importantly, because genistein also reduced hippocampal lead accumulation, the in vivo neuroprotection may reflect both reduced target-tissue lead burden and improved glutathione-related redox homeostasis. Untargeted metabolomics identified 59 genistein-responsive metabolites enriched mainly in glutathione metabolism, oxidative phosphorylation, and ascorbate/aldarate metabolism, linking metabolic remodeling to behavioral recovery and reduced oxidative-apoptotic injury. In HT22 cells, blockade of glutathione synthesis by buthionine sulfoximine markedly weakened genistein-mediated cytoprotection, mitochondrial membrane potential recovery, and apoptosis inhibition. Collectively, genistein mitigates lead-induced hippocampal neurotoxicity and cognitive impairment by restoring glutathione-centered redox–mitochondrial homeostasis, supporting its further development as a mechanistically defined dietary candidate for environmental pollutant-associated neural injury.