Circulating MicroRNAs as Biomarkers for Ischemic Heart Disease: A Systematic Review and Gene Set Enrichment Analysis

Yasmine Alcibahy¹Radwan Darwish^1*Ghena Abu-Sharia²Quinten Maes³Omar Elgamassy¹

• ¹Royal College of Surgeons in Ireland (Bahrain), Al Muharraq, Bahrain
• ²Alfaisal University, Riyadh, Saudi Arabia
• ³University of Groningen, Groningen, Netherlands

Ischemic heart disease (IHD) remains a major global health burden, emphasizing the need for early, non-invasive diagnostic biomarkers. This systematic review evaluated the potential of microRNAs (miRNAs) in this context. Following PRISMA guidelines, we searched PubMed, Scopus, and Web of Science up to June 31, 2024. Thirty-eight studies met the eligibility criteria. From these, five miRNAs, miR-126, miR-21, miR-145, miR-92a, and miR-155, were most frequently and consistently reported across diverse IHD subtypes. While their expression varied across studies, they were recurrently dysregulated, suggesting involvement in IHD-related processes rather than a uniform diagnostic pattern. We used miRTarBase to retrieve validated gene targets and performed gene set enrichment analysis (GSEA) via Enrichr using the BioPlanet, KEGG, and Panther libraries. Targets were enriched in p53, TGF-β, and FoxO signaling, apoptosis, and angiogenesis, core pathways in vascular injury, remodeling, and immune activation. Enrichment in several cancer-related pathways further reflects the shared molecular mechanisms between tumorigenesis and atherosclerosis. Functional annotation using TAM 2.0 supported these findings, linking the selected miRNAs to smooth muscle differentiation, cytokine signaling, and key transcription factors such as SMAD4, STAT3, and AP-1. Together, these results suggest that a multi-marker panel combining these miRNAs may offer greater diagnostic utility than individual markers. Larger prospective studies are warranted to validate their clinical applicability in IHD screening and risk stratification.