Endothelial EPAS1 as a prognostic and therapeutic target in acute myocardial infarction: integrative bioinformatics, Mendelian randomization and experimental validation.

BACKGROUND: Acute myocardial infarction (AMI), characterized by acute myocardial necrosis due to coronary occlusion, is a life-threatening cardiovascular event. Ferroptosis critically contributes to ischemic injury, yet its causal regulators in AMI, particularly in endothelial cells, remain elusive. METHODS: We integrated AMI transcriptomics with summary-data-based Mendelian randomization (SMR) and colocalization to identify causal ferroptosis-related transcription factor (TF). A miRNA-TF-mRNA regulatory network was constructed via miRNA-TF and TF-target prediction. Subsequent analyses, including TF binding site prediction, GSEA, GeneMANIA, gene-disease and gene-drug association screening, phenome-wide association study (PheWAS), ROC curve evaluation, and RT-qPCR validation in HUVECs, were performed to characterize the molecular mechanisms of this axis in AMI. RESULTS: EPAS1 was identified as a causal ferroptosis-related TF in AMI (P SMR < 0.05; P HEIDI > 0.05). We constructed a ferroptosis-related miRNA-TF-mRNA network and identified a novel endothelial-specific axis, hsa-miR-138-5p/EPAS1/BACH1. RT-qPCR in HUVECs validated the GEO-derived expression patterns of axis components. PheWAS further revealed no significant adverse phenotypic associations for genes within this axis, supporting the druggability of approved compounds targeting it. CONCLUSION: This study identifies EPAS1 as a TF with suggestive genetic links to AMI risk and characterizes a novel endothelial-enriched hsa-miR-138-5p/EPAS1/BACH1 regulatory axis governing ferroptosis. This molecular cascade provides candidate molecular clues for subsequent preclinical research into cardioprotective strategies targeting ferroptosis in AMI.