Decoding Potential Cuproptosis-Related Genes in Sarcopenia: A Multi-Omics Network Analysis

Sarcopenia is a common age-related skeletal muscle disorder that lacks diagnostic and therapeutic options. Emerging evidence suggests that cuproptosis, a copper-dependent form of regulated cell death, contributes to muscle atrophy, yet the underlying associations remain poorly understood. To address this gap, we integrated two GEO datasets (GSE1428 and GSE25941) for differential expression analysis and applied weighted gene co-expression network analysis (WGCNA) to identify disease-related modules. Cuproptosis-related genes (CRGs) from GeneCards database were intersected with DEGs and WGCNA gene modules to obtain sarcopenia-associated cuproptosis DEGs (SAR-CUP DEGs). Functional enrichment was performed using GO, KEGG, GSEA and GSVA. Hub genes were further identified through three machine learning algorithms (LASSO, RF, and SVM). Regulatory networks were constructed via NetworkAnalyst and GeneMANIA database. A diagnostic model was also developed and later validated in an independent dataset (GSE136344). Experimental validation was performed in a D-galactose-induced sarcopenia cell model. We identified 367 DEGs and 7 co-expression modules, among which 14 SAR-CUP DEGs were mainly enriched in mitochondrial energy metabolism pathways. Machine learning methods highlighted <i>SLC25A12</i> and <i>PABPC4</i> as hub genes. Regulatory network analysis revealed key modulators, such as FOXC1, miR-16-5p, GOT2, and GOT1. Diagnostic performance analysis demonstrated strong predictive value for <i>SLC25A12</i> (AUC = 0.879) and <i>PABPC4</i> (AUC = 0.858), and RT-qPCR confirmed their downregulation in the sarcopenia cell model (<i>p</i> < 0.01). In conclusion, <i>SLC25A12</i> and <i>PABPC4</i> are promising biomarkers linking copper metabolism dysregulation with sarcopenia, offering potential targets for diagnosis and therapy.