Xunan Jia, Huijun Chen
Myocardial ischemia–reperfusion injury (MIRI) is driven by dynamic metabolic disturbances that extend beyond adenosine triphosphate depletion and encompass mitochondrial dysfunction, redox imbalance, calcium overload, iron dysregulation, lipid peroxidation, and inflammatory activation. These alterations regulate multiple forms of programmed cell death, including apoptosis, necroptosis, ferroptosis, pyroptosis, and mitochondrial permeability transition pore-dependent necrosis. However, these pathways are frequently investigated in isolation, despite sharing common upstream metabolic triggers and interacting through overlapping signaling networks and execution mechanisms. This conceptual narrative review summarizes current evidence regarding how metabolic states influence the activation thresholds, temporal dynamics, and relative contributions of regulated cell-death pathways during myocardial ischemia and reperfusion. We propose a metabolism-gated framework in which cellular energy status, mitochondrial integrity, redox homeostasis, calcium burden, iron availability, lipid composition, and inflammatory priming collectively determine context-dependent susceptibility and dominance of specific death pathways. Autophagy and mitophagy are considered regulators of metabolic adaptation and mitochondrial quality control rather than independent cell-death modalities. Current evidence indicates extensive pathway co-activation and crosstalk, with the predominant mechanisms varying according to reperfusion stage, myocardial region, cell type, metabolic background, and experimental model. In contrast, definitive switching between terminal death pathways within the same cell population remains insufficiently established. Functional pathway switching should therefore be distinguished from concurrent expression of pathway-associated markers or shared upstream signaling events and should be demonstrated through time-resolved multi-pathway analyses, selective genetic or pharmacological inhibition of an initially activated pathway, compensatory activation of an alternative execution pathway, and greater protection achieved through combined inhibition compared with single-pathway targeting. This framework further emphasizes the limitations of attributing myocardial injury to a single death mechanism based solely on pathway-associated biomarkers. Integrating metabolic profiling with cell-type-specific and spatially resolved assessments of death-pathway execution may enable more precise mechanistic classification and support the development of rational combination therapies. Thus, metabolism-gated pathway selection and interpathway crosstalk represent a testable framework for elucidating the heterogeneity of MIRI and for designing context-dependent cardioprotective strategies.