Targeting STAT3 to Modulate the Effectiveness of Cardioprotective Conditioning Strategies Against Myocardial Ischemia–Reperfusion Injury in Subjects With Diabetic Cardiomyopathy

Myocardial ischemia-reperfusion injury (MIRI) is a major cause of cardiovascular morbidity and mortality. Reperfusion, although essential for myocardial restoration, can paradoxically exacerbate injury through oxidative stress, calcium overload, mitochondrial permeability transition pore opening and inflammatory infiltration. The vulnerability to MIRI is substantially amplified in subjects with diabetes mellitus, where chronic hyperglycemia, insulin resistance, and the resulting oxidative stress and low-grade inflammation impair endogenous cardioprotective mechanisms and worsen postinfarction outcomes. Ischemic conditioning strategies, including preconditioning and postconditioning, serve as powerful innate methods to mitigate MIRI by exposing the myocardium to brief, sublethal ischemic episodes that activate crucial prosurvival signalling pathways. Among these pathways, the survivor activating factor enhancement pathway, which is mediated predominantly by signal transducer and activator of transcription 3 (STAT3), and the reperfusion injury salvage kinase pathway, which involves AKT and ERK, are particularly important. However, in many models of diabetes, diabetes-induced STAT3 dysfunction may disrupt these protective pathways, often making conditioning stimuli less effective. The precise mechanisms underlying this impairment remain incompletely understood. Additionally, paradoxical changes in STAT3 expression have been reported, and key posttranslational modifications of STAT3 have not yet been investigated in the context of diabetic MIRI. This review provides a critical appraisal of the role, regulatory mechanisms and therapeutic potential of STAT3 in ischemic conditioning in patients with diabetes and discusses strategies aimed at restoring cardioprotection in this high-risk population.