Key result
Hexokinase 2 protects against cardiac ischemia and hypertrophy by enhancing glycolysis and mitochondrial function.
Why the study?
Under pathological conditions, glycolysis is increased, and accumulating evidence indicates that hexokinase 2 confers cardioprotection in ischemia, hypertrophy, and regeneration.
Design
Review
Targeting the Hexokinase 2-mitochondrial association offers a potential therapeutic strategy for improving cardioprotection in ischemic and hypertrophic conditions.
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.
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Gao et al. (2026) studied this question. Hexokinase 2 increases glycolysis to protect the heart against ischemia, hypertrophy, and supports regeneration by enhancing mitochondrial function under pathological conditions.
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