2. Academic Validation
  3. ZNRF2 is essential for gliomagenesis through orchestrating glycolysis and acts as a promising therapeutic target in glioma

ZNRF2 is essential for gliomagenesis through orchestrating glycolysis and acts as a promising therapeutic target in glioma

  • J Transl Med. 2025 Feb 14;23(1):185. doi: 10.1186/s12967-025-06202-1.
Yunlan Xi # 1,  Qingqing Yang # 1,  Yixuan Wang # 2,  Wenzhe An # 1,  Xuewei Huang 1,  Cuiyun Sun 1,  Wenjun Luo 1,  Cuijuan Shi 1,  Qian Wang 1,  Hongli Pan 2,  Qiang Chen 3 4,  Xuebing Li 2,  Dan Hua 5 6,  Shizhu Yu 7 8,  Xuexia Zhou 9 10
Affiliations

Affiliations

  • 1 Department of Neuropathology, Tianjin Neurological Institute, Tianjin Key Laboratory of Injuries, Variations, and Regeneration of the Nervous System, Key Laboratory of Post-trauma Neuro-repair and Regeneration in Central Nervous System of Education Ministry, Tianjin Medical University General Hospital, Tianjin, P. R. China.
  • 2 Tianjin Key Laboratory of Lung Cancer Metastasis and Tumor Microenvironment, Department of Lung Cancer Surgery, Tianjin Lung Cancer Institute, Tianjin Medical University General Hospital, Tianjin, China.
  • 3 Department of Respiratory and Critical Medicine, Tianjin Chest Hospital, Tianjin, P.R. China.
  • 4 Tianjin Medical University, Tianjin, P.R. China.
  • 5 Department of Neuropathology, Tianjin Neurological Institute, Tianjin Key Laboratory of Injuries, Variations, and Regeneration of the Nervous System, Key Laboratory of Post-trauma Neuro-repair and Regeneration in Central Nervous System of Education Ministry, Tianjin Medical University General Hospital, Tianjin, P. R. China. kila1126@hotmail.com.
  • 6 Department of Neuropathology, Tianjin Neurological Institute, Tianjin Medical University General Hospital, 154 Anshan Road, Tianjin, 300052, China. kila1126@hotmail.com.
  • 7 Department of Neuropathology, Tianjin Neurological Institute, Tianjin Key Laboratory of Injuries, Variations, and Regeneration of the Nervous System, Key Laboratory of Post-trauma Neuro-repair and Regeneration in Central Nervous System of Education Ministry, Tianjin Medical University General Hospital, Tianjin, P. R. China. tjyushizhu@163.com.
  • 8 Department of Neuropathology, Tianjin Neurological Institute, Tianjin Medical University General Hospital, 154 Anshan Road, Tianjin, 300052, China. tjyushizhu@163.com.
  • 9 Department of Neuropathology, Tianjin Neurological Institute, Tianjin Key Laboratory of Injuries, Variations, and Regeneration of the Nervous System, Key Laboratory of Post-trauma Neuro-repair and Regeneration in Central Nervous System of Education Ministry, Tianjin Medical University General Hospital, Tianjin, P. R. China. xxzhou@tmu.edu.cn.
  • 10 Department of Neuropathology, Tianjin Neurological Institute, Tianjin Medical University General Hospital, 154 Anshan Road, Tianjin, 300052, China. xxzhou@tmu.edu.cn.
  • # Contributed equally.
PMID: 39953597 DOI: 10.1186/s12967-025-06202-1
Abstract

Background: Improving glioma treatment effectiveness requires a thorough understanding of gliomagenesis. Emerging evidences have proved that zinc and ring finger 2 (ZNRF2) contributes to development of various human malignancies. Nevertheless, a comprehensive study of ZNRF2's role in glioma is absent currently.

Methods: Utilizing open resources from Chinese Glioma Genome Atlas (CGGA), Gene Expression Omnibus (GEO), The Cancer Genome Atlas (TCGA), Connectivity Map (cMap) and Other bioinformatic tools, we systematically examined the expression, clinical significance, prognostic value, regulated biological processes, immune infiltration, and potential inhibitors of ZNRF2 in gliomas. Functional experiments were also performed to validate its oncogenic roles in glioblastoma (GBM) cells.

Results: Our findings revealed that ZNRF2 expression was elevated in gliomas compared to normal brains, and its higher levels were correlated with increased grades and worse patient prognosis. The immune analysis suggested that immunotherapies targeting immune checkpoint genes could be beneficial for glioma patients with elevated ZNRF2 expression. Endogenous ZNRF2 knockdown impaired GBM cell proliferation, G2/M cell cycle progression and glycolysis, which was revealed by reduced ATP, pyruvic acid, lactic acid levels and less glucose uptake. Finally, we identified methylprednisolone (MP) as a potential ZNRF2 inhibitor and validated its anti-glioma effects in vitro. MP also enhanced the sensitization of GBM cells to temozolomide (TMZ), the primary chemotherapeutic agent for GBM in clinic.

Conclusions: Taken together, our study demonstrated ZNRF2 as an essential tumor-promoting factor by favoring GBM cell proliferation and glycolysis. Our findings suggested that ZNRF2 might serve as a novel independent prognostic biomarker and promising therapeutic target for glioma patients.

Keywords

Glioma; Glycolysis; Prognosis; Therapeutic target; ZNRF2.

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