Advanced glycation end products and RAGE signaling in diabetic cardiomyopathy: distinct mechanisms, human evidence, and translational barriers.

Diabetic cardiomyopathy refers to myocardial structural, functional, and metabolic abnormalities enriched in people with diabetes that are not fully explained by obstructive epicardial coronary artery disease, significant valvular disease, or other established cardiac conditions. In clinical practice, diabetic myocardial dysfunction frequently overlaps with obesity, hypertension, chronic kidney disease, coronary microvascular dysfunction, and heart failure with preserved ejection fraction (HFpEF)-type cardiometabolic phenotypes. Among the mechanisms implicated in this condition, advanced glycation end products (AGEs) and receptor for advanced glycation end products (RAGE) signaling constitute a biologically plausible framework linking chronic hyperglycemia and dicarbonyl stress to myocardial injury. This review distinguishes RAGE-independent AGE-mediated injury, including extracellular matrix cross-linking and intracellular protein modification, from RAGE-dependent multiligand signaling, which may amplify oxidative, inflammatory, mitochondrial, calcium-handling, endothelial, and profibrotic responses. We further discuss RAGE as a multiligand pattern-recognition receptor and its interactions with danger signaling, innate immune pathways, and inflammasome activation within a broader inflammatory-oxidative network. In addition, we evaluate therapeutic strategies aimed at reducing glycation burden, interrupting matrix cross-linking, or inhibiting receptor-related signaling, and assess circulating and tissue-related biomarkers for phenotypic stratification and therapeutic monitoring. The review further considers methylglyoxal, glyoxal, 3-deoxyglucosone, and glyoxalase-1-dependent detoxification as components of dicarbonyl stress. Although experimental evidence supports biological plausibility, human evidence remains predominantly associative, circulating biomarkers lack cardiac specificity, and DCM-specific therapeutic trials are scarce. Future studies should use phenotype-enriched, multimodal biomarker strategies and mechanism-matched endpoints to determine whether selected patient subgroups may benefit from AGE- or RAGE-directed intervention.