†These authors contributed equally.
Background: Ferroptosis is a form of iron-dependent regulated cell
death, and prior work has highlighted the potential utility of
ferroptosis-inducing agents as tools to treat heart failure (HF). To date,
however, no detailed examinations of the prognostic utility of
ferroptosis-related genes (FRGs) in HF have been conducted.
Methods: We used established genomic identification of FRGs for
total samples in the gene expression omnibus (GEO) database, screened for differentially expressed FRGs,
performed protein-protein interaction analysis and functional analysis of HF
immune microenvironment subtypes. Subsequently, we applied tools to calculate
immune cell infiltration, compare immune cell, immune response genomic and
HLA gene differences between subtypes, and perform candidate drug
identification. Finally, preliminary in vivo validation of the screened
central genes was performed in animal models. Results: FRGs
were compared between samples from HF and healthy control donors, revealing 62 of
these genes to be differentially expressed as a function of HF status. HF
patient-derived tissues exhibited significant changes in the expression of
HLA genes, increase immune cell infiltration, and higher levels of other
immune-related genes within the associated immune microenvironment. These FRGs
were then leveraged to establish two different immune-related subtypes of HF
based on clustering analysis results, after which these subtypes were
characterized in further detail. Functional enrichment analyses revealed the
identified differentially expressed genes to be enriched in key immune-related
pathways including the primary immunodeficiency, natural killer cell-mediated
cytotoxicity, Fc