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Peer-reviewedCC BY 4.0International Journal of Molecular Sciences

The m6A Reader IGF2BP2 Drives Depressive-like Behaviors Through m6A-Dependent Repression of Astrocytic GLUT1 and Glucose Metabolism

  • Zijing Liu1,2
  • Jiayu Li1,2
  • Kexin Meng1,2
  • Yuwen Su1,2
  • Yaqun Zhang3,4,5
  • Jianbo Xiu1,6
6 affiliations
  1. 1Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing 100005, China
  2. 2State Key Laboratory of Common Mechanism Research for Major Diseases, Beijing 100005, China
  3. 3Department of Urology, Peking University First Hospital, Beijing 100034, China
  4. 4Beijing Key Laboratory of Urogenital Diseases (Male) Molecular Diagnosis and Treatment Center, Beijing 100034, China
  5. 5National Urological Cancer Center, Beijing 100034, China
  6. 6State Key Laboratory of Complex, Severe, and Rare Diseases, Beijing 100005, China
Open at sourceDOICite

Abstract

Major depressive disorder (MDD) is a severe psychiatric condition with complex etiology and limited therapeutic targets. In this study, we identify the m6A reader protein IGF2BP2 as a critical epigenetic regulator in depression. We demonstrate that IGF2BP2 expression is significantly upregulated in the hippocampus of both MDD patients and mice subjected to chronic unpredictable mild stress (CUMS). Further, hippocampal knockdown of Igf2bp2 ameliorated depressive-like behaviors in mice. Mechanistically, we demonstrated that the IGF2BP2 protein, specifically in astrocytes, binds to the mRNA of glucose transporter 1 (GLUT1) and regulates the expression of GLUT1 in an m6A-dependent manner, mainly by promoting its decay, leading to impaired astrocytic glucose uptake. Moreover, overexpression of Glut1 rescued both glucose metabolic deficits and depressive-like behaviors. Taken together, our findings reveal a previously unrecognized IGF2BP2-GLUT1 axis in the pathogenesis of depression and highlight its potential as a therapeutic target for antidepressant intervention.

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Cite

BibTeXRIS
BibTeX
@article{liu2026reader,
  title = {{The m6A Reader IGF2BP2 Drives Depressive-like Behaviors Through m6A-Dependent Repression of Astrocytic GLUT1 and Glucose Metabolism}},
  author = {Zijing Liu and Jiayu Li and Kexin Meng and Yuwen Su and Yaqun Zhang and Jianbo Xiu},
  journal = {International Journal of Molecular Sciences},
  year = {2026},
  month = oct,
  doi = {10.3390/ijms27219803},
  url = {https://www.mdpi.com/1422-0067/27/21/9803},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - The m6A Reader IGF2BP2 Drives Depressive-like Behaviors Through m6A-Dependent Repression of Astrocytic GLUT1 and Glucose Metabolism
AU  - Zijing Liu
AU  - Jiayu Li
AU  - Kexin Meng
AU  - Yuwen Su
AU  - Yaqun Zhang
AU  - Jianbo Xiu
PY  - 2026
DA  - 2026/10/31
JO  - International Journal of Molecular Sciences
DO  - 10.3390/ijms27219803
UR  - https://www.mdpi.com/1422-0067/27/21/9803
AB  - Major depressive disorder (MDD) is a severe psychiatric condition with complex etiology and limited therapeutic targets. In this study, we identify the m6A reader protein IGF2BP2 as a critical epigenetic regulator in depression. We demonstrate that IGF2BP2 expression is significantly upregulated in the hippocampus of both MDD patients and mice subjected to chronic unpredictable mild stress (CUMS). Further, hippocampal knockdown of Igf2bp2 ameliorated depressive-like behaviors in mice. Mechanistically, we demonstrated that the IGF2BP2 protein, specifically in astrocytes, binds to the mRNA of glucose transporter 1 (GLUT1) and regulates the expression of GLUT1 in an m6A-dependent manner, mainly by promoting its decay, leading to impaired astrocytic glucose uptake. Moreover, overexpression of Glut1 rescued both glucose metabolic deficits and depressive-like behaviors. Taken together, our findings reveal a previously unrecognized IGF2BP2-GLUT1 axis in the pathogenesis of depression and highlight its potential as a therapeutic target for antidepressant intervention.
SN  - 1422-0067
ER  -