2. Academic Validation
  3. NDRG2 upregulation induces astrocytic apoptosis via AKT inhibition and FoxO3a-Puma activation in depression

NDRG2 upregulation induces astrocytic apoptosis via AKT inhibition and FoxO3a-Puma activation in depression

  • Commun Biol. 2025 Nov 17;8(1):1585. doi: 10.1038/s42003-025-08968-y.
Zhuoqun Wang 1,  Jiayu Yang 1,  Huiliang Zhang 1,  Dan Ke 1,  Lun Zhang 1 2,  Yi Liu 1,  Yiwen Lai 1,  Yiren Zhang 1,  Xuan Qin 1,  Jie Yang 1,  Mengyao Kang 1,  Wenqi Yang 1,  Xiaochuan Wang 3 4 5,  Ji Zeng 6,  Rong Liu 7 8 9
Affiliations

Affiliations

  • 1 Department of Pathophysiology, Key Laboratory of Ministry of Education/Hubei Province for Neurological Disorders, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
  • 2 Department of Clinical Laboratory, Wuhan Fourth Hospital, Wuhan, China.
  • 3 Department of Pathophysiology, Key Laboratory of Ministry of Education/Hubei Province for Neurological Disorders, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. [email protected].
  • 4 Shenzhen Huazhong University of Science and Technology Research Institute, Shenzhen, China. [email protected].
  • 5 Hubei Key Laboratory of Cognitive and Affective Disorders, Institutes of Biomedical Sciences, School of Medicine, Jianghan University, Wuhan, China. [email protected].
  • 6 Department of Clinical Laboratory, Wuhan Fourth Hospital, Wuhan, China. [email protected].
  • 7 Department of Pathophysiology, Key Laboratory of Ministry of Education/Hubei Province for Neurological Disorders, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. [email protected].
  • 8 Shenzhen Huazhong University of Science and Technology Research Institute, Shenzhen, China. [email protected].
  • 9 Institute for Brain Research, Wuhan Center of Brain Science, Huazhong University of Science and Technology, Wuhan, China. [email protected].
PMID: 41249439 DOI: 10.1038/s42003-025-08968-y
Abstract

The loss of astrocytes represents a key pathological hallmark of major depressive disorder, yet its mechanisms remain elusive. Here, we identified NDRG2 as a critical regulator of astrocyte Apoptosis in depression. NDRG2 expression is upregulated in depression models, concomitant with astrocyte loss. Overexpression of NDRG2 in astrocytes triggered Apoptosis and depressive-like behaviors, with inhibition of Akt and activation of FoxO3a-Puma apoptotic signaling pathway. Mechanistically, NDRG2 recruits PP2A to Akt, facilitating its dephosphorylation and subsequent inactivation, then promotes the nuclear translocation of FoxO3a, leading to the transcriptional activation of the pro-apoptotic factor Puma. Crucially, NDRG2 knockdown in astrocytes effectively prevented astrocytic Apoptosis, with effective rescue of depressive-like phenotypes. These findings reveal a key mechanism of astrocyte death in depression, wherein NDRG2 functions as an adaptor to promote PP2A-mediated Akt dephosphorylation, thereby initiating the pro-apoptotic signaling pathway, and disclose a druggable pathway for developing antidepressants targeting astrocyte preservation.

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