Narrative review discusses iron-dependent ferroptosis in cardiac microvascular endothelial cells during myocardial ischemia-reperfusion

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Frontiers in Medicine Published May 7, 2026 Medically reviewed May 7, 2026 DOI ↗ By Dr. Amelia Tan, PhD · Internal Medicine & Chronic Disease

Key Takeaway

Consider emerging iron-chelation and antioxidant strategies for myocardial ischemia-reperfusion in microvascular endothelial cells.

This narrative review focuses on the mechanisms of iron-dependent ferroptosis and dysregulated iron homeostasis within cardiac microvascular endothelial cells during myocardial ischemia-reperfusion. The scope of the discussion centers on cellular pathways rather than clinical trial data. The authors do not report a specific sample size, setting, or follow-up duration for the clinical scenarios described.

The authors synthesize potential therapeutic approaches including iron chelation, the use of radical-trapping antioxidants, reinforcement of cystine import and antioxidant systems, and microvascular barrier-stabilizing strategies. These suggestions are presented as emerging opportunities rather than established clinical practices. No specific primary or secondary outcomes were reported in the source material.

The review does not provide data on adverse events, tolerability, or discontinuations. Limitations acknowledged by the authors regarding the lack of clinical trial data are implied by the absence of reported safety metrics. The certainty of these therapeutic suggestions is not explicitly graded in the source text. Practice relevance is limited to theoretical discussion of mechanisms and potential future directions.

Study Details

Study typeSystematic review

EvidenceLevel 1

PublishedMay 2026

View Original Abstract ↓

Despite successful epicardial recanalization, effective tissue reperfusion frequently remains limited by cardiac microvascular dysfunction, including endothelial swelling, barrier leakage, leukocyte-platelet adhesion, and microvascular obstruction/no-reflow. A growing body of work links these microcirculatory phenotypes to iron-driven phospholipid peroxidation and ferroptosis. During ischemia-reperfusion, dysregulated iron handling expands the labile iron pool through iron import, heme/iron release, and ferritinophagy, while antioxidant defenses become compromised. Cardiac microvascular endothelial cells (CMECs) appear particularly vulnerable to this iron-dependent lipid peroxidation cascade, and ferroptotic or sublethally injured CMECs can propagate microvascular injury by weakening junctional integrity, increasing edema, and exacerbating perfusion heterogeneity that ultimately amplifies cardiomyocyte hypoxia and death. In this review, we summarize the mechanistic basis of endothelial ferroptosis under iron dyshomeostasis, propose an integrated CMEC-centered framework connecting iron dysregulation to microcirculatory injury during reperfusion, and discuss emerging therapeutic opportunities, such as iron chelation, radical-trapping antioxidants, reinforcement of cystine import/antioxidant systems, and microvascular barrier-stabilizing strategies aimed at preserving endothelial function and improving microvascular reperfusion.