2. Academic Validation
  3. Ubiquitination-mediated upregulation of glycolytic enzyme MCT4 in promoting astrocyte reactivity during neuroinflammation

Ubiquitination-mediated upregulation of glycolytic enzyme MCT4 in promoting astrocyte reactivity during neuroinflammation

  • J Neuroinflammation. 2025 Apr 30;22(1):126. doi: 10.1186/s12974-025-03453-z.
Luting Yang # 1,  Chunqing Hu # 2,  Xiaowen Chen # 2,  Mengru Sun # 2,  Jie Zhang 2,  Zhe Feng 2,  Tingting Cui 2,  Ruyi Zhu 2,  Xin Zhang 2,  Yanxin Xiao 2,  Ye Gong 3,  Yang Yang 2,  Qian Zhang 2,  Yaling Zhang 2,  Yaping Yan 4
Affiliations

Affiliations

  • 1 Key Laboratory of the Ministry of Education for Medicinal Resources and Natural Pharmaceutical Chemistry, National Engineering Laboratory for Resource Development of Endangered Crude Drugs in Northwest of China, College of Life Sciences, Shaanxi Normal University, Xi'an, 710119, China. yangluting@snnu.edu.cn.
  • 2 Key Laboratory of the Ministry of Education for Medicinal Resources and Natural Pharmaceutical Chemistry, National Engineering Laboratory for Resource Development of Endangered Crude Drugs in Northwest of China, College of Life Sciences, Shaanxi Normal University, Xi'an, 710119, China.
  • 3 Department of Experimental Surgery, Tangdu Hospital, Air Force Medical University, Xi'an, 710038, China.
  • 4 Key Laboratory of the Ministry of Education for Medicinal Resources and Natural Pharmaceutical Chemistry, National Engineering Laboratory for Resource Development of Endangered Crude Drugs in Northwest of China, College of Life Sciences, Shaanxi Normal University, Xi'an, 710119, China. yaping.yan@snnu.edu.cn.
  • # Contributed equally.
PMID: 40307809 DOI: 10.1186/s12974-025-03453-z
Abstract

One of the histopathological hallmarks of neuroinflammatory diseases such as multiple sclerosis (MS) is the emergence of astrocyte reactivity. Accumulating evidence suggests that excessive glycolysis may lead to astrocyte reactivity and contribute to neuroinflammatory responses. However, the intricate mechanisms underlying astrocyte metabolic reprogramming towards glycolysis remain largely unknown. Here, we conducted in vitro experiments using primary astrocytes and in vivo studies in an experimental autoimmune encephalomyelitis (EAE) mouse model of multiple sclerosis (MS). We observed increased astrocytic expression of MCT4, a key glycolytic regulator, in EAE mice. MCT4 enhanced astrocyte reactivity through promoting glycolysis and proliferation, mediated primarily by activation of the NF-κB and c-Myc signaling pathways. Notably, we report a novel regulatory mechanism in which the E3 ubiquitin Ligase TRIM7 regulates MCT4 levels via ubiquitination. In mice, blockade of astrocyte MCT4 expression by intracerebroventricular injection of lentivirus alleviated disease severity of EAE mice. The results suggest that targeting glycolysis, specifically through the inhibition of MCT4 expression, might be effective in reducing astrocyte reactivity, neuroinflammation and demyelination occurring in MS and relating neuroinflammatory diseases.

Keywords

Astrocyte; Experimental autoimmune encephalomyelitis; Glycolysis; Proliferation; Ubiquitination.

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