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This study utilized six PD datasets from the GEO database, designating one for internal training and the remaining five for external validation. Various analytical methods, such as Gene Set Enrichment Analysis (GSEA), immune infiltration studies, and differential expression analysis, were employed to pinpoint differentially expressed genes (DEGs). The research also applied Weighted Gene Co-expression Network Analysis (WGCNA) to identify module genes, followed by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses. By intersecting DEGs with cuproptosis-related genes (CRGs), differentially expressed cuproptosis-related genes (DECRGs) were identified and assessed using Receiver Operating Characteristic (ROC) curves. Further analysis led to the discovery of differentially expressed cuproptosis-mitochondrial dysfunction-related genes (DEC-MDRGs), which were validated and subjected to additional scrutiny. The study concluded with predictions of potential therapeutic drugs. The findings revealed 6685 DEGs and 31 distinct modules, with gene functions predominantly enriched in immune-related pathways. Twelve DECRGs, recognized as high-diagnostic-potential hub genes (AUC\u2009&gt;\u20090.9), were identified for early PD diagnosis. Additionally, eight DEC-MDRGs were found to be expressed across various neural cells. The miRNA network highlighted the significance of miR-4632 and miR-637. In a MPTP-induced mouse model of PD, differential gene expression was confirmed through gene and protein analysis. Transmission electron microscopy (TEM) uncovered mitochondrial alterations in SH-SY5Y cells. Potential PD treatments, including NADH, Radicipol, and Glycine, were also identified. In summary, advancements in PD prevention, diagnosis, and treatment can be achieved by modulating copper metabolism and mitochondrial function, thereby enhancing the quality of life for patients.<\/jats:p>","DOI":"10.1371\/journal.pone.0327550","type":"journal-article","created":{"date-parts":[[2025,7,17]],"date-time":"2025-07-17T17:44:00Z","timestamp":1752774240000},"page":"e0327550","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":1,"title":["Cuproptosis-related genes associated with mitochondrial dysfunction in Parkinson\u2019s 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