Integrated Multi-omics and Experimental Validation Reveal FDX1/LIAS-Mediated Cuproptosis as a Potential Driver of Diabetic Kidney Disease.

C opper is an essential trace element involved in mitochondrial metabolism and redox regulation, and its dysregulation has been increasingly linked to metabolic disorders. However, its specific role in diabetic kidney disease (DKD) remains unclear. In this study, we conducted an integrated analysis combining bulk RNA-seq, single-cell RNA sequencing, and spatial transcriptomics to investigate the involvement of cuproptosis-related genes in DKD. We identified consistent upregulation of FDX1 and LIAS, two key regulators of copper-induced cell death, in the kidneys of diabetic mice. These genes were predominantly localized to metabolically active tubular segments, including the distal convoluted tubule and cortical thick ascending limb. Clinically, urinary copper levels were significantly elevated in DKD patients, indicating systemic copper imbalance. Protein-level validation confirmed increased expression of FDX1 and LIAS as well as decreased expression of cleaved and monomeric form of DLAT in db/db mouse kidney tissue, suggesting impaired mitochondrial lipoylation, a molecular hallmark of cuproptosis. Collectively, these findings provide multi-level evidence that copper overload and activation of cuproptosis-associated pathways may contribute to tubular injury in DKD, offering new insight into trace element-related mechanisms in the pathology of diabetic kidney disease.