Lactate dehydrogenase A inhibition-induced metabolic reprogramming combined with targeted ceria nanozymes protects against myocardial ischemia-reperfusion injury.

BACKGROUND

Myocardial ischemia-reperfusion injury remains a major challenge in cardiovascular therapy, largely driven by oxidative stress, mitochondrial dysfunction, and metabolic imbalance. Lactate dehydrogenase A (LDHA) inhibition has emerged as a potential strategy to reprogram myocardial metabolism and enhance antioxidant capacity, but its effects on redox homeostasis during ischemia-reperfusion remain incompletely understood. This study aimed to evaluate the therapeutic efficacy of combining the LDHA inhibitor GNE-140 with cerium oxide nanozymes using a targeted drug delivery system for myocardial ischemia-reperfusion injury.

RESULTS

GNE-140 reduced lactate production and promoted a metabolic shift toward the pentose phosphate pathway, leading to increased nicotinamide adenine dinucleotide phosphate (NADPH) levels and enhanced endogenous antioxidant capacity in cardiomyocytes. However, elevated NADPH also increased susceptibility to excessive reactive oxygen species generation. To overcome this limitation, a cardiac-targeted nanoplatform was developed by loading GNE-140 and in situ biomineralized cerium oxide into mesoporous polydopamine nanoparticles functionalized with cardiac homing peptides. This system enabled sustained drug release and effective reactive oxygen species scavenging. In vitro experiments using hypoxia/reoxygenation-injured cardiomyocytes demonstrated improved cell viability, preserved mitochondrial function, and reduced oxidative stress with the combined treatment. In a mouse model of myocardial ischemia-reperfusion injury, the nanoplatform significantly reduced myocardial reactive oxygen species levels and apoptosis, improved cardiac function, and attenuated adverse myocardial remodeling.

CONCLUSIONS

This study demonstrates that combining metabolic reprogramming through LDHA inhibition with antioxidant nanozyme therapy provides effective protection against myocardial ischemia-reperfusion injury. The targeted co-delivery of GNE-140 and cerium oxide nanozymes offers a promising strategy to mitigate oxidative stress, preserve mitochondrial integrity, and improve both acute and long-term cardiac outcomes following ischemic injury.