Integrative analyses and validation of ferroptosis-related genes and mechanisms associated with cerebrovascular and cardiovascular ischemic diseases

Abstract

Background: There has been a gradual increase in the occurrence of cardiovascular and cerebrovascular ischemic diseases, particularly as comorbidities. Yet, the mechanisms underlying these diseases remain unclear. Ferroptosis has emerged as a potential contributor to cardio-cerebral ischemic processes. Therefore, this study investigated the shared biological mechanisms between the two processes, as well as the role of ferroptosis genes in cardio-cerebral ischemic damage, by constructing co-expression modules for myocardial ischemia (MI) and ischemic stroke (IS) and a network of protein-protein interactions, mRNA-miRNA, mRNA-transcription factors (TFs), mRNA-RNA-binding proteins (RBPs), and mRNA-drug interactions.

Results: The study identified seven key genes, specifically ACSL1, TLR4, ADIPOR1, G0S2, PDK4, HP, PTGS2, and subjected them to functional enrichment analysis during ischemia. The predicted miRNAs were found to interact with 35 hub genes, and interactions were observed between 11 hub genes and 30 TF transcription factors. Additionally, 10 RBPs corresponding to 16 hub genes and 163 molecular compounds corresponding to 30 hub genes were identified. This study also clarified the levels of immune infiltration between MI and IS and different subtypes. Finally, we identified four hub genes, including TLR4, by using a diagnostic model constructed by Least Absolute Shrinkage and Selection Operator (LASSO) regression analysis; ADIPOR1, G0S2, and HP were shown to have diagnostic value for the co-pathogenesis of MI and cerebral ischemia by both validation test data and RT-qPCR assay.

Conclusions: To the best our knowledge, this study is the first to utilize multiple algorithms to comprehensively analyze the biological processes of MI and IS from various perspectives. The four hub genes, TLR4, ADIPOR1, G0S2, and HP, have proven valuable in offering insights for the investigation of shared injury pathways in cardio-cerebral injuries. Therefore, these genes may serve as diagnostic markers for cardio-cerebral ischemic diseases.

Keywords: Cardiovascular ischemic diseases; Cerebrovascular ischemic diseases; Common pathway of injury; Diagnostic marker; Ferroptosis; Machine algorithms.