Frontiers in Pharmacology · Published 2026-08-04 · DOI 10.3389/fphar.2026.1893164
Xiaona Yang, Zhongyan Li, Lingxian Guo, Jingru Li, Huan Cheng, Xue Guan, Najie Wen, Huawei Wang, Longjun Li, Lihong Yang, Yancui Zhu, Luqiao Wang
BackgroundAcute 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.MethodsWe 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.ResultsEPAS1 was identified as a causal ferroptosis-related TF in AMI (PSMR < 0.05; PHEIDI > 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.ConclusionThis 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.
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Yang, X., Li, Z., Guo, L., et al. (2026). Endothelial EPAS1 as a prognostic and therapeutic target in acute myocardial infarction: integrative bioinformatics, Mendelian randomization and experimental validation. Frontiers in Pharmacology. https://doi.org/10.3389/fphar.2026.1893164