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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\u2010limiting 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\u2010mitochondrial association. These findings provide new insights for harnessing HK2 to improve cardiac protection and design effective therapeutic strategies.<\/jats:p>","DOI":"10.1002\/biof.70082","type":"journal-article","created":{"date-parts":[[2026,2,11]],"date-time":"2026-02-11T11:21:54Z","timestamp":1770808914000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Hexokinase 2\u2010Driven Cardioprotection in Ischemia, Hypertrophy, and Regeneration: From Underlying Mechanisms to Clinical Translation"],"prefix":"10.1002","volume":"52","author":[{"ORCID":"https:\/\/orcid.org\/0009-0003-7671-6267","authenticated-orcid":false,"given":"Junying","family":"Gao","sequence":"first","affiliation":[{"name":"Key Laboratory of Evolution and Marine Biodiversity (Ministry of Education) and Institute of Evolution and Marine Biodiversity Ocean University of China  Qingdao China"},{"name":"College of Fisheries Ocean University of China  Qingdao China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jun","family":"Qi","sequence":"additional","affiliation":[{"name":"Laboratory Department Shandong Public Health Clinical Center Affiliated to Shandong University  Jinan Shandong China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhaodi","family":"Zheng","sequence":"additional","affiliation":[{"name":"School of Forensics and Laboratory Medicine Jining Medical University  Jining Shandong China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-4716-0054","authenticated-orcid":false,"given":"Haoran","family":"Qi","sequence":"additional","affiliation":[{"name":"Department of Spine Surgery, Spinal Deformity Center The Second Xiangya Hospital of Central South University  Changsha Hunan China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2026,2,11]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.1161\/01.RES.56.3.377"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.yjmcc.2021.08.003"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11886-000-0071-9"},{"key":"e_1_2_11_5_1","doi-asserted-by":"publisher","DOI":"10.1093\/cvr\/cvx017"},{"key":"e_1_2_11_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ydbio.2021.01.020"},{"key":"e_1_2_11_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cophys.2019.04.004"},{"key":"e_1_2_11_8_1","doi-asserted-by":"publisher","DOI":"10.1093\/cvr\/cvr015"},{"key":"e_1_2_11_9_1","first-page":"68","article-title":"Aerobic vs Anaerobic Metabolism During Ischemia in Heart Muscle","volume":"76","author":"Das D. 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