Prospects for adiponectin-based therapeutics in myocardial ischemia reperfusion injury

Adiponectin is an adipocyte-derived hormone with broad cardiometabolic benefits, circulating at high levels in healthy individuals but reduced in obesity, diabetes, and cardiovascular disease. Low adiponectin concentrations are strongly associated with coronary artery disease, myocardial infarction, myocardial ischemia-reperfusion injury (MIRI), and heart failure. MIRI remains a major unmet need in contemporary ST-segment-elevation myocardial infarction (STEMI) care. Although reperfusion is essential in limiting ischemic myocardial necrosis, it causes deleterious effects such as impaired carbohydrate oxidation, excessive fatty-acid oxidation, intracellular acidosis, calcium (Ca²⁺) overload, oxidative/nitrative stress, and mitochondrial fragmentation, that expand infarct size, worsen microvascular obstruction, and fuel adverse ventricular remodeling. Activation of the adiponectin-adiponectin receptor (AdipoR) axis directly counteracts these processes by stimulating adenosine monophosphate-activated protein kinase (AMPK)-dependent metabolic rebalancing, restoring mitochondrial fusion-fission homeostasis, enhancing oxidative capacity, reducing inducible nitric oxide synthase (iNOS-) and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase-mediated injury, improving endothelial nitric oxide (NO) bioavailability, and enhancing microvascular perfusion. In animal models, adiponectin or its mimetics consistently reduced infarct size, improved myocardial function, and attenuated apoptosis, inflammation, and no-reflow. A growing array of therapeutic strategies has emerged, each bringing its own pharmacologic nuances and implications for translation to the clinic. This review summarizes current strategies to enhance adiponectin action, highlights the progress in peptide and small-molecule mimetics, and discusses future directions for clinical translation in cardiometabolic diseases.