2. Academic Validation
  3. Inhibition of microglial Slc2a5 attenuates ischemic brain injury

Inhibition of microglial Slc2a5 attenuates ischemic brain injury

  • Metabolism. 2026 Feb:175:156429. doi: 10.1016/j.metabol.2025.156429.
Daosheng Ai 1,  Baoshan Qiu 2,  Xing-Jun Chen 1,  Fengzhi Li 3,  Di Yao 4,  Huijie Mi 1,  Jun-Liszt Li 1,  Bing Zhou 5,  Jian Zuo 6,  Yilong Wang 7,  Woo-Ping Ge 8,  Wenzhi Sun 9
Affiliations

Affiliations

  • 1 Academy for Advanced Interdisciplinary Studies (AAIS), Peking University, Beijing 100871, China; Chinese Institute for Brain Research, Beijing, Beijing 102206, China.
  • 2 Chinese Institute for Brain Research, Beijing, Beijing 102206, China; Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing 100071, China.
  • 3 Chinese Institute for Brain Research, Beijing, Beijing 102206, China; State Key Laboratory of Cognitive Neuroscience and Learning, Beijing Normal University, Beijing 100875, China.
  • 4 Chinese Institute for Brain Research, Beijing, Beijing 102206, China; School of Basic Medical Sciences, Capital Medical University, Beijing 100069, China.
  • 5 School of Engineering Medicine, Beihang University, Beijing 100191, China.
  • 6 Ting Therapeutics, Inc., 6868 Nancy Ridge Dr., San Diego, CA 92121, USA.
  • 7 Chinese Institute for Brain Research, Beijing, Beijing 102206, China; Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing 100071, China. Electronic address: [email protected].
  • 8 Chinese Institute for Brain Research, Beijing, Beijing 102206, China; Beijing Institute for Brain Research, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 102206, China; Changping Laboratory, Beijing, 102206, China. Electronic address: [email protected].
  • 9 Chinese Institute for Brain Research, Beijing, Beijing 102206, China; School of Basic Medical Sciences, Capital Medical University, Beijing 100069, China. Electronic address: [email protected].
PMID: 41205649 DOI: 10.1016/j.metabol.2025.156429
Abstract

Acute ischemic stroke (AIS) is one of the leading causes of mortality and disability globally. Despite its complex pathological mechanisms, effective neuroprotective strategies are still lacking in clinical practice. Microglia and their metabolic processes play a pivotal role in the pathogenesis of AIS, yet the impact and underlying mechanisms of microglial fructose metabolism remain unclear. In this study, we identified Slc2a5 (also known as Glut5), a crucial regulator of fructose metabolism in microglia, as a key factor contributing to the early progression of AIS. Conditional deletion of Slc2a5 in microglia significantly alleviated brain injury in a mouse model of AIS. Single-cell transcriptomic (scRNA-seq) analysis demonstrated that the deletion of Slc2a5 promoted the differentiation of microglia into stroke-associated subpopulations with neuroprotective properties. Moreover, in vitro experiments indicated that this microglial differentiation process was primarily mediated by the activity of Pyruvate Kinase M2 (PKM2). Collectively, our findings unveil a novel microglial Slc2a5-mediated fructose metabolism pathway that exacerbates brain injury after AIS. This study provides evidence for SLC2A5 as a promising therapeutic target for the clinical treatment of AIS by offering insights into its critical role in microglial metabolism and neuroprotection.

Keywords

Acute ischemic stroke; Microglia; Slc2a5.

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