Role of Mitophagy-Related Genes in Chronic Thromboembolic Pulmonary Hypertension based on Single-cell RNA Sequencing analysis

Abstract Background The significance of mitophagy in various diseases has been extensively studied in the field of biomedical research. However, its role in chronic thromboembolic pulmonary hypertension (CTEPH) remains unexplored. The purpose of this study was to investigate the correlation between mitophagy and key CTEPH genes, laying the groundwork for subsequent research endeavors. Methods Utilizing six GEO datasets, we identified core mitophagy genes for CTEPH through differential gene analysis, WGCNA, cytohubba, LASSO, and SVM-RFE. We validated the model and genes' diagnostic value with external data and confirmed hub gene expression. Single-cell analysis with MAESTRO, PCA, KNN, and Louvain algorithms identified variable features and cell clusters, with Monocle 3 and CellChat analyzing cell differentiation and intercellular communication. Results We discovered nine CTEPH-related mitophagy genes (GOLGA3, NFE2L1, FOS, ELL2, USO1, MAPK8, AMFR, BCL2L1, and JUN), whose diagnostic value was externally validated. Single-cell data revealed high expression of these genes in fibroblasts, myofibroblasts, and endothelial cells. The NOTCH pathway was notably active in myofibroblasts, with the JAG1-NOTCH3 pair significantly influencing the CTEPH progression. Conclusion Mitophagy genes are implicated in CTEPH pathogenesis, with myofibroblasts potentially driving disease progression via the NOTCH pathway, particularly through the JAG1-NOTCH3 interaction. This study lays the groundwork for deeper investigation into CTEPH mechanisms.