The pathogenesis of DLD-mediated cuproptosis induced spinal cord injury and its regulation on immune microenvironment

Abstract

IntroductionSpinal cord injury (SCI) is a severe central nervous system injury that leads to significant sensory and motor impairment. Copper, an essential trace element in the human body, plays a vital role in various biological functions and is strictly regulated by copper chaperones and transporters. Cuproptosis, a novel type of metal ion-induced cell death, is distinct from iron deprivation. Copper deprivation is closely associated with mitochondrial metabolism and mediated by protein fatty acid acylation.MethodsIn this study, we investigated the effects of cuproptosis-related genes (CRGs) on disease progression and the immune microenvironment in acute spinal cord injury (ASCI) patients. We obtained the gene expression profiles of peripheral blood leukocytes from ASCI patients using the Gene Expression Omnibus (GEO) database. We performed differential gene analysis, constructed protein-protein interaction networks, conducted weighted gene co-expression network analysis (WGCNA), and built a risk model.ResultsOur analysis revealed that dihydrolipoamide dehydrogenase (DLD), a regulator of copper toxicity, was significantly associated with ASCI, and DLD expression was significantly upregulated after ASCI. Furthermore, gene ontology (GO) enrichment analysis and gene set variation analysis (GSVA) showed abnormal activation of metabolism-related processes. Immune infiltration analysis indicated a significant decrease in T cell numbers in ASCI patients, while M2 macrophage numbers were significantly increased and positively correlated with DLD expression.DiscussionIn summary, our study demonstrated that DLD affects the ASCI immune microenvironment by promoting copper toxicity, leading to increased peripheral M2 macrophage polarization and systemic immunosuppression. Thus, DLD has potential as a promising biomarker for ASCI, providing a foundation for future clinical interventions.

Identification of cuproptosis-related gene clusters and immune cell infiltration in major burns based on machine learning models and experimental validation

“…Studies have reported that cuprotosis plays a role in signal transduction and regulates the etiology, severity, and progression of cancer. It not only plays a role in chronic diseases but also participates in the occurrence and development of various acute diseases, such as acute myocardial infarction and acute spinal cord injury (7)(8)(9). Cuprotosis, an intervention target for copper metabolism disorders, may be a novel approach for treating various diseases.…”