Hexokinase 2‐Driven Cardioprotection in Ischemia, Hypertrophy, and Regeneration: From Underlying Mechanisms to Clinical Translation

The heart is the most energy-demanding organ in the body and has a dynamically adaptable metabolic state. Under normal conditions, the adult heart primarily relies on mitochondrial oxidative phosphorylation for ATP generation, whereas glycolysis supplies a minor portion of the energy. However, under pathological conditions, glycolysis is increased, and mitochondrial oxidative phosphorylation is reduced. Hexokinase 2 (HK2) is the first rate-limiting enzyme in the glycolytic pathway in cardiomyocytes. Accumulating evidence in recent years has indicated that HK2 confers protection to the heart under pathological conditions. In this review, we summarize the roles of HK2 in cardiac ischemia/hypoxia, hypertrophy, and regeneration, focusing on its functions and the molecular mechanisms underlying these processes. Additionally, we discuss the application of pharmacologically targeting HK2 in pathological models and explore the potential value and future research directions of targeting the HK2-mitochondrial association. These findings provide new insights for harnessing HK2 to improve cardiac protection and design effective therapeutic strategies.