Role of DLAT‐Mediated Neuron Cuproptosis in Cognitive Impairment Induced by Lead Exposure

ABSTRACT Cuproptosis, a newly identified form of copper‐dependent regulated cell death, plays a crucial role in the pathogenesis of neurodegenerative diseases. However, whether cuproptosis is involved in lead (Pb)‐induced cognitive impairment and its underlying mechanisms remains unclear. Herein, using Pb‐exposed rat models and HT22 neuronal cell models, we found that Pb exposure led to dose‐dependent increases in copper levels in both hippocampus tissue and blood. These increases were accompanied by disorganized hippocampus neuron structures, nuclear shrinkage, and were correlated with cognitive decline. Then, the IMAC approach was employed to isolate copper‐associated proteins, followed by proteomic sequencing. The differentially expressed copper‐binding proteins were significantly enriched in biological processes related to cuproptosis. Notably, the expressions of key cuproptosis‐associated proteins—DLAT, DLST, FDX1, and LIAS—were markedly reduced in the hippocampus and neuron cells following Pb exposure, with DLAT showing the most pronounced decrease. Moreover, tetrathiomolybdate (TTM) treatment, a cuproptosis inhibitor, significantly attenuated Pb‐induced neuron death. Overexpression of DLAT effectively reversed Pb‐induced neuron cuproptosis, as evidenced by decreased intracellular copper and H 2 O 2 levels and increased ATP and CAT levels. Additionally, a preliminary investigation on Pb‐exposed workers revealed that blood Dlat mRNA expression partially mediated the relationship between blood Pb levels and cognitive performance scores. Collectively, these findings suggest that cuproptosis contributes to Pb‐induced cognitive impairment, with DLAT playing a key regulatory role in this process.