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1573-73654112025Dec17Metabolic brain diseaseMetab Brain DisGLUT1 and GLUT3 in brain glucose metabolism: mechanisms, regulation, and implications for metabolic disorders.3310.1007/s11011-025-01753-0Brain energy metabolism primarily depends on glucose, which serves as the primary energy source for neuronal activity. Glucose entry into the brain is mediated by glucose transporters, the major isoforms of which are GLUT1 and GLUT3. GLUT1 is responsible for delivering glucose to the brain parenchyma, while GLUT3, with its high affinity for glucose, ensures glucose uptake by neurons. Growing evidence indicates that disturbed glucose metabolism is closely associated with impaired brain function and the progression of neurological diseases, and regulating these transporters may be a potential therapeutic strategy to restore metabolic balance. This review focuses on the current understanding of the functions and regulation of GLUT1 and GLUT3. We first examine their distribution and their distinct contributions to glucose utilization, then summarize how pathological factors such as ischemia, hypoxia, oxidative stress, and neuroinflammation alter the expression and activity of these transporters. At the molecular level, we highlight the multiple signaling pathways involved in the regulation of glucose transporters. The PI3K/Akt, HIF-1α, AMPK, and mTOR pathways, along with microRNA-mediated mechanisms, influence the expression and activity of GLUT1 or GLUT3, respectively, in diverse physiological and pathological contexts. We also discuss evidence for pathway crosstalk, including interactions between PI3K/Akt, mTOR, and HIF-1α, as well as AMPK-mTOR coupling, which may provide additional regulatory insights. In summary, despite significant progress, critical gaps remain in linking upstream signaling to transporter dynamics and therapeutic effects. A deeper understanding of the regulatory networks underlying glucose metabolism will more accurately capture the complexity of disease-related metabolic regulation and may reveal novel therapeutic targets for intervening in glucose metabolism disorders.© 2025. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.LiXintongXInstitute of traditional Chinese medicine, Heilongjiang University of traditional Chinese Medicine, Harbin, Heilongjiang, China.YangMengMCollege of medicine, Heilongjiang University of traditional Chinese Medicine, Harbin, Heilongjiang, China.WangTiantianTCollege of medicine, Heilongjiang University of traditional Chinese Medicine, Harbin, Heilongjiang, China.LiuSiyuSInstitute of traditional Chinese medicine, Heilongjiang University of traditional Chinese Medicine, Harbin, Heilongjiang, China.College of medicine, Heilongjiang University of traditional Chinese Medicine, Harbin, Heilongjiang, China.HanHuaH0000-0002-7042-5827College of medicine, Heilongjiang University of traditional Chinese Medicine, Harbin, Heilongjiang, China. hanhua@hljucm.edu.cn.DongPeiliangP0000-0003-2173-089XInstitute of traditional Chinese medicine, Heilongjiang University of traditional Chinese Medicine, Harbin, Heilongjiang, China. dongpeiliang@hljucm.edu.cn.eng82474289Foundation for Innovative Research Groups of the National Natural Science Foundation of China82474289Foundation for Innovative Research Groups of the National Natural Science Foundation of China82474289Foundation for Innovative Research Groups of the National Natural Science Foundation of China82474289Foundation for Innovative Research Groups of the National Natural Science Foundation of China82474289Foundation for Innovative Research Groups of the National Natural Science Foundation of ChinaLH2023H071Natural Science Foundation of Heilongjiang ProvinceLH2023H071Natural Science Foundation of Heilongjiang ProvinceLH2023H071Natural Science Foundation of Heilongjiang ProvinceLH2023H071Natural Science Foundation of Heilongjiang ProvinceLH2023H071Natural Science Foundation of Heilongjiang ProvinceJournal ArticleReview20251217
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