Discovery of Genes Related to Cuproptosis and Mitophagy to Improve Myocardial Infarction Diagnosis and Treatment.

Abstract

Introduction: Emerging evidence links cuproptosis and mitophagy to the progression of myocardial infarction (MI). This study explored cuproptosis- and mitophagy-related gene modules in MI, aiming to identify potential biomarkers to improve MI management.

Methods: The GSE66360 dataset, containing 50 control and 49 MI samples, was obtained from GEO. Differentially expressed genes (DEGs) were identified using the "limma" 3.42.2 package, and pathway differences were analyzed via gene set enrichment analysis (GSEA). After clustering gene modules related to cuproptosis and mitophagy using weighted gene co-expression network analysis (WGCNA), core modular genes were selected. LASSO regression and random forest were employed for feature selection. Immune microenvironment profiling was conducted using singlesample GSEA (ssGSEA) and CIBERSORT algorithms. Finally, potential therapeutic targets were identified using DSigDB and molecular docking.

Results: We identified the DEGs between MI and control samples. GSEA analysis showed that these genes were associated with the cell cycle, glycolysis, and the inflammatory signaling pathway. The dark green module identified by WGCNA was correlated with both cuproptosis and mitophagy and enriched in oxidative phosphorylation and immune processes. By combining the core modular genes and DEGs, six hub genes were selected using LASSO and random forests. A 3-gene diagnostic model established based on GPCPD1, S100A8, and CD55 achieved an Area under the Curve (AUC) of 0.959. The three genes were upregulated in MI and correlated with immune infiltration. Molecular docking showed Corbadrine and Dicyclomine were potential therapeutic agents targeting CD55.

Discussion: This study highlights the broader implications of linking cuproptosis and mitophagy in MI, proposing a novel perspective on mitochondrial dysfunction as a central hub connecting metabolic stress, immune dysregulation, and cell death. The identified core genes-S100A8, CD55, and GPCPD1-not only serve as potential diagnostic markers but may represent functional nodes at the intersection of copper-dependent cell death and mitochondrial quality control. Their strong association with inflammatory cell infiltration suggests that these genes could influence the post-MI immune microenvironment, potentially affecting both injury progression and repair. Moreover, the feasibility of targeting CD55, as indicated by molecular docking, opens new avenues for therapeutic interventions to modulate complement activation and inflammation. While the findings are computationally derived, they generate testable hypotheses about crosstalk between emerging cell death pathways and immune-metabolic pathways in MI, underscoring the need for future experimental studies to validate these interactions and explore their translational potential in cardiovascular disease.

Conclusion: The core genes (GPCPD1, S100A8, and CD55) identified in this study not only served as potential diagnostic markers but were also functional nodes in copper-dependent cell death, contributing to MI treatment.