Identification of Ferroptosis-related Genes and Its CeRNA Network in Hypertrophic Cardiomyopathy Based on Bioinformatic Analysis

Abstract Background: Hypertrophic Cardiomyopathy (HCM) is a comman heritable cardiomyopth which is strongly associated with the risk of sudden death and heart failure in young adults. The underlying mechanisms are still not well defined. Growing evidence suggests that ferroptosis plays an important role in the development and occurrence of cardiovascular disease. This study explored the relationship between ferroptosis-related genes and hypertrophic cardiomyopathy and the lncRNA-associated competing endogenous RNA (ceRNA) network of these genes based on a bioinformatics method. Methods: Four datasets (GSE180313, GSE36961, GSE188324, GSE197218) about HCM were collected from GEO database. HCM-related module genes were identified through weighted gene co-expression network analysis (WGCNA) by R WGCNA package. Ferroptosis-related genes were downloaded from the ferroptosis-related database FerrDb V2. The overlap was performed to obtain the module genes associated with ferroptosis. The Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed using R clusterprofiler package. Protein–Protein Interaction (PPI) Network was constructed through the STRING online analysis tool. Cytoscape with CytoHubba was used to identify the hub genes. The Expression of hub genes in cardiac tissue was examined by the statistic program SPSS 27.0. Then the lncRNA-associated competing endogenous RNA (ceRNA) network was constructed. Results: 64 ferroptosis-related genes associated with HCM by WGCNA and FerrDB V2 were obtained. Enrichment analysis revealed that pathways related to iron ion homeostasis and lipid metabolism were the most highly enriched terms. Seven hub genes (PPARG, CD44, ACO1, SIRT1, CDKN2A, ADIPOQ, and TFRC) were obtained by PPI network construction and CytoHubba plug-in of Cytoscape. Through validation in other gene expression datasets, we obtained five hub-genes which were further screened by ceRNA network construction to obtain two key regulatory lncRNAs: NUTM2B-AS1, XIST and two hub-genes: PPARG, CD44. Conclusions: LncRNA XIST, and NUTM2B-AS1 regulated the hub genes (PPARG, and CD44) through a ceRNA regulatory network and may regulate the pathogenesis of HCM in a ferroptosis regulatory manner.