Resistant hypertension (RH) is one of the high-risk types within the spectrum of hypertensive disorders, characterized by a complex pathogenesis. To identify hub differentially expressed genes (DEGs) associated with this disease, this study performed transcriptome sequencing on 30 blood samples collected in 2022 from the Affiliated Hospital of Shandong University of Traditional Chinese Medicine and Jinan Fifth People's Hospital (comprising 10 hypertensive patients, 10 RH patients, and 10 healthy controls). Using DESeq2 analysis, 731 DEGs were initially screened. Subsequently, weighted gene co-expression network analysis (WGCNA) identified 2 modules significantly associated with RH (containing 1,944 genes). Taking the intersection of these module genes and the DEGs yielded 229 key DEGs. Gene Ontology (GO) enrichment analysis revealed that these key DEGs were significantly enriched in biological processes such as drug catabolic process, cellular components like hemoglobin complex, and molecular functions including peroxidase activity. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis indicated that these DEGs were associated with pathways such as the VEGF signaling pathway and mitophagy. A protein-protein interaction (PPI) network was further constructed. Using the cytohubba plugin in Cytoscape software, hub genes were identified by integrating the results from 12 algorithms (taking the intersection of the top 20 genes from each algorithm), preliminarily determining, andas the hub DEGs. Validation by qRT-PCR confirmed that the expression changes of1 andwere consistent with the sequencing results. This study suggests that the development of RH involves the synergistic action of multiple genes, and perturbations in hub genes (,) and related pathways (VEGF signaling pathway, mitophagy) may play significant roles in the disease process. These findings provide new insights for a deeper understanding of the pathological mechanisms underlying RH. GATA1, EPB42, ANK1SNCA GATA EPB42GATA1EPB42
