Comprehensive analysis of ferroptosis-related hub gene signatures as a potential pathogenesis and therapeutic target...

Introduction: The molecular mechanism of systemic sclerosis (SSc) remains unclear. Ferroptosis participates in a series of cell activities, such as inflammatory progression, by regulating cell death; unfortunately, there aren't many research that discuss the connection between ferroptosis and SSc.Objectives: This study used bioinformatics analysis to report a potential relationship between ferroptosis and SSc.Methods: The SSc and control datasets GSE125362 and GSE76807 were obtained from the gene expression omnibus database. The differentially expressed genes (DEGs) were identified using the R software. By the Venn diagram, ferroptosis DEGs were detected. The chosen candidate genes were then subjected to analyses of protein-protein interactions, gene ontology enrichment, and Kyoto Encyclopedia of Genes and Genomes pathway enrichment. With the Molecular Complex Detection plugin program, the hub genes were investigated. A multifactor regulatory network was constructed depending on key hub genes, and immune infiltration was also evaluated. Finally, quantitative real-time polymerase chain reaction (RT-PCR) and enzyme linked immunosorbent assay were used to validate the bioinformatic results.Results: Twenty-four ferroptosis-related differentially expressed genes were detected in patients with SSc versus the normal controls. The biological processes of FRGs in patients with SSc focused on the negative regulation of cell proliferation and inflammatory response. The signaling pathways were enriched in necroptosis. The core genes of SSc were CYBB, IL-6, NOX4,TLR4, CXCL2, JUN, and LY96. Three miRNAs, two lncRNAs, and five transcription factors were predicted. The evaluation of immune infiltration showed that the number of activated natural killer (NK) cells increased in SSc skin tissues, whereas the number of resting dendritic, NK, and mast cells decreased. The bioinformatics prediction results from the mRNA chip were in line with the expression levels of IL-6 and CYBB.Conclusions: Necroptosis and ferroptosis were upregulated in patients with SSc and involved in modulating cell proliferation, differentiation, and migration. IL-6 and CYBB are key ferroptosis-related genes in SSc. Ferroptosis and related genes might be promising targets in the treatment of SSc.