Gender-Specific Key Genes and Pathways in Heart Failure with Reduced Ejection Fraction: A Bioinformatics Analysis

Heart failure (HF) is a global health challenge, affecting approximately 23 million people, with around half of these cases classified as heart failure with reduced ejection fraction (HFrEF). HFrEF poses a significant burden on morbidity and mortality rates, and its prevalence demonstrates a marked sex disparity, with men being more affected than women. This study aimed to uncover the key genes and signaling pathways associated with the sex-specific differences observed in HFrEF. We began by retrieving the GSE161472 gene expression dataset from the Gene Expression Omnibus database. Using R software, we identified differentially expressed genes (DEGs) based on disease state and sex. From this, we focused on the overlapping DEGs and mapped their interactions in a protein-protein interaction network. Functional enrichment analyses were carried out using the Metascape platform, and Cytoscape was utilized to identify hub genes. Additionally, box plots and Receiver Operating Characteristic (ROC) curves were created to assess the performance of these hub genes. Furthermore, we explored key microRNAs (miRNAs), transcription factors (TFs), and potential pharmacological agents involved in the regulation of the identified hub genes. Our analysis revealed 1,249 DEGs between male and female HFrEF patients, with 714 upregulated and 535 downregulated in males, strongly associated with the Hippo signaling pathway. Six genes—NDUFA2, NDUFB10, NDUFB3, NDUFB7, NDUFV1, and UQCRH—were identified as hub genes. We also identified numerous miRNAs, TFs, and drug interactions linked to these six hub genes, shedding light on the complex molecular mechanisms underlying sex differences in HFrEF. Our findings indicate that the Hippo signaling pathway may play a crucial role in the sex-specific differences observed in HFrEF, and that the hub genes NDUFA2, NDUFB10, NDUFB3, NDUFB7, NDUFV1, and UQCRH may be pivotal in the sexually dimorphic progression of the disease, making them promising targets for therapeutic intervention.