Integrated analysis and validation of ferroptosis-related genes and immune infiltration in acute myocardial infarction.

BACKGROUND: Acute myocardial infarction (AMI) is indeed a significant cause of mortality and morbidity in individuals with coronary heart disease. Ferroptosis, an iron-dependent cell death, is characterized by the accumulation of intracellular lipid peroxides, which is implicated in cardiomyocyte injury. This study aims to identify biomarkers that are indicative of ferroptosis in the context of AMI, and to examine their potential roles in immune infiltration. METHODS: Firstly, the GSE59867 dataset was used to identify differentially expressed ferroptosis-related genes (DE-FRGs) in AMI. We then performed gene ontology (GO) and functional enrichment analysis on these DE-FRGs. Secondly, we analyzed the GSE76591 dataset and used bioinformatic methods to build ceRNA networks. Thirdly, we identified hub genes in protein-protein interaction (PPI) network. After obtaining the key DE-FRGs through the junction of hub genes with ceRNA and least absolute shrinkage and selection operator (LASSO). ImmucellAI was applied to estimate the immune cell infiltration in each sample and examine the relationship between key DE-FRGs and 24 immunocyte subsets. The diagnostic performance of these genes was further evaluated using the receiver operating characteristic (ROC) curve analysis. Ultimately, we identified an immune-related ceRNA regulatory axis linked to ferroptosis in AMI. RESULTS: Among 56 DE-FRGs identified in AMI, 41 of them were integrated into the construction of competitive endogenous RNA (ceRNA) networks. TLR4 and PIK3CA were identified as key DE-FRGs and PIK3CA was confirmed as a diagnostic biomarker for AMI. Moreover, CD4_native cells, nTreg cells, Th2 cells, Th17 cells, central-memory cells, effector-memory cells, and CD8_T cells had higher infiltrates in AMI samples compared to control samples. In contrast, exhausted cells, iTreg cells, and Tfh cells had lower infiltrates in AMI samples. Spearman analysis confirmed the correlation between 24 immune cells and PIK3CA/TLR4. Ultimately, we constructed an immune-related regulatory axis involving XIST and OIP5-AS1/miR-216a/PIK3CA. CONCLUSION: Our comprehensive analysis has identified PIK3CA as a robust and promising biomarker for this condition. Moreover, we have also identified an immune-related regulatory axis involving XIST and OIP5-AS1/miR-216a/PIK3CA, which may play a key role in regulating ferroptosis during AMI progression.

Noncoding RNAs regulating ferroptosis in cardiovascular diseases: novel roles and therapeutic strategies.

The morbidity and mortality rates of cardiovascular diseases (CVDs) are increasing; thus, they impose substantial health and economic burdens worldwide, and effective interventions are needed for immediate resolution of this issue. Recent studies have suggested that noncoding RNAs (ncRNAs) play critical roles in the occurrence and development of CVDs and are potential therapeutic targets and novel biomarkers for these diseases. Newly discovered modes of cell death, including necroptosis, pyroptosis, apoptosis, autophagy-dependent cell death and ferroptosis, also play key roles in CVD progression. However, ferroptosis, which differs from the other aforementioned forms of regulated cell death in terms of cell morphology, biochemistry and inhereditability, is a unique iron-dependent mode of nonapoptotic cell death induced by abnormal iron metabolism and excessive accumulation of iron-dependent lipid peroxides and reactive oxygen species (ROS). Increasing evidence has confirmed that ncRNA-mediated ferroptosis is involved in regulating tissue homeostasis and CVD-related pathophysiological conditions, such as cardiac ischemia/reperfusion (I/R) injury, myocardial infarction (MI), atrial fibrillation (AF), cardiomyopathy and heart failure (HF). In this review, we summarize the underlying mechanism of ferroptosis, discuss the pathophysiological effects of ncRNA-mediated ferroptosis in CVDs and provide ideas for effective therapeutic strategies.