Redox imbalance and glutathione metabolism disruption drive neodymium - induced neurotoxicity in microglia.

Neodymium (Nd), a rare earth element widely used in clean energy and electronic technologies, has raised increasing concern for its potential neurotoxic effects. Microglia, the primary immune cells of the central nervous system, are particularly sensitive to environmental chemicals. In this study, we investigated the effects of neodymium nitrate [Nd(NO₃)₃] on microglial physiology and metabolism using integrated cellular and metabolomic analyses. Nd exposure disrupted microglial homeostasis by impairing proliferation, suppressing phagocytosis, and promoting M1-type proinflammatory polarization. Accumulation of reactive oxygen species (ROS) and depletion of glutathione indicated pronounced oxidative stress and redox imbalance, accompanied by mitochondrial damage and ATP loss. Untargeted metabolomics revealed concentration-dependent metabolic reprogramming, with early perturbations in glutathione metabolism and the glyoxalase system as central events driving oxidative and inflammatory responses. Among the differentially altered metabolites, S-lactoylglutathione and glutathione showed the highest sensitivity and strongest correlation with inflammatory phenotypes. Downregulation of glyoxalase enzymes (GLO1 and GLO2) further confirmed compromised antioxidant capacity and impaired detoxification. Collectively, these findings demonstrate that Nd induces microglial dysfunction through disruption of the glutathione-glyoxalase redox axis, providing new mechanistic insight into how rare earth element exposure may contribute to neurotoxicity.