Humanized hiPSC Platforms for I/R Injury: Advancing Toward Precision Cardioprotection

Myocardial ischemia-reperfusion (I/R) injury remains a major contributor to infarct expansion, adverse remodeling, and heart failure despite timely coronary revascularization. The repeated failure of cardioprotective interventions that were effective in animal models has exposed a persistent translational gap. Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) and engineered cardiac platforms preserve donor-specific human genetic backgrounds, provide scalable cell sources, and offer experimentally tractable systems for studying selected mechanisms of I/R injury. Recent advances in electrical, mechanical, metabolic, and endocrine maturation, together with engineered heart tissues (EHTs), cardiac organoids, and perfused heart-on-a-chip platforms, have improved the ability to model cardiomyocyte stress, calcium overload, mitochondrial dysfunction, oxidative injury, and multicellular crosstalk. Single-cell and spatial omics, CRISPR-based perturbation, and artificial intelligence (AI)-assisted high-content phenotyping further enable state-resolved and mechanistically testable analyses of vulnerable cardiac cell populations. In this narrative review, we synthesize recent progress in hiPSC-based myocardial I/R modeling, critically evaluate the strengths and limitations of current platforms, and discuss their use in mechanism-guided drug screening, cardiotoxicity assessment, and patient-specific preclinical modeling. We emphasize that these systems are not yet substitutes for clinical validation or whole-organ physiology. Their current value lies in providing controllable, human-relevant preclinical models that can prioritize mechanisms, identify candidate interventions, and support better-designed translational cardioprotection studies.