Diabetic cardiomyopathy (DCM) is one of the crucial causes leading to heart failure and adverse outcomes in patients with diabetes mellitus; however, effective strategies targeting its molecular pathological mechanisms and therapies are currently lacking. DCM is primarily characterized by early diastolic dysfunction, cardiomyocyte apoptosis, and fibrosis. Its disease progression is relatively insidious, eventually evolving into heart failure with preserved ejection fraction. The intrinsic metabolic environment of diabetes markedly exacerbates oxidative stress, and the accumulated polyunsaturated fatty acids within cardiomyocytes are highly susceptible to lipid peroxidation, leading to the excessive generation of 4-hydroxy-2-nonenal (4-HNE). The pivotal role of this reactive aldehyde in promoting the progression of DCM has been extensively demonstrated in animal, cellular, and clinical models. However, its subcellular targets and the underlying molecular mechanisms remain inadequately elucidated. Organelles, as central executors of diverse intracellular functions, may serve as potential sites of 4-HNE-induced interference and therapeutic targeting. This article focuses on the central role of 4-HNE in triggering energy depletion, calcium overload, autophagic flux blockade, and ferroptosis through its interactions among mitochondria, endoplasmic reticulum, lysosomes, and other organelles. On the basis of existing evidence, potentially translatable therapeutic avenues include ALDH2 activators, G protein–coupled receptor 40 (GPR40) agonists, mitochondria-targeted antioxidants and ferroptosis inhibitors. The aim is to provide a theoretical foundation and reference for the clinical identification of myocardial injury in DCM, model replication, and the development of targeted intervention strategies.

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.