2. Academic Validation
  3. Targeting VCP with V8 suppresses glioblastoma development via formation of aggregates and disruption of mitophagy flux

Targeting VCP with V8 suppresses glioblastoma development via formation of aggregates and disruption of mitophagy flux

  • Cell Oncol (Dordr). 2026 Jan 8;49(1):21. doi: 10.1007/s13402-025-01149-3.
Xuejun Cao # 1,  Yishen Li # 1,  Bin Guo 1,  Yan Liu 2,  Baoshuai Wang 1,  Hao Wang 1,  Jingbo Lu 1,  Libin Wei 1,  Yuan Gao 1,  Yongjian Guo 3,  Tao Wu 4
Affiliations

Affiliations

  • 1 State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Carcinogenesis and Intervention, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing, 210009, People's Republic of China.
  • 2 Department of Pathology, BaogangHospital of InnerMongolia, The Third Affiliated Hospital of Inner Mongolia Medical University, 20 Shaoxian Road, Kun District, Baotou, 014010, People's Republic of China.
  • 3 School of Biopharmacy, China Pharmaceutical University Jiangning Campus, 639 Longmian Avenue, Jiangning District, Nanjing, 211198, People's Republic of China. [email protected].
  • 4 State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Carcinogenesis and Intervention, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing, 210009, People's Republic of China. [email protected].
  • # Contributed equally.
PMID: 41505038 DOI: 10.1007/s13402-025-01149-3
Abstract

Background: Glioblastoma (GBM) is a highly lethal malignancy with limited therapeutic options. Identifying effective therapeutic targets and developing corresponding drugs remain unmet clinical needs.

Purpose: This study aimed to investigate the expression and role of VCP in GBM, as well as the anti-GBM activity and underlying mechanisms of V8, a wogonin-derived small molecule.

Methods: The expression of VCP in GBM cells and its correlation with glioma malignancy were analyzed. The binding of V8 to VCP was verified, and the effects of V8 on VCP function, cellular proteostasis, mitochondrial status, Mitophagy process, and lysosomal integrity were evaluated to clarify its anti-GBM mechanisms.

Results: VCP is highly expressed in GBM cells and correlates with glioma malignancy. V8 exerts anti-GBM activity by binding to the D1 domain of VCP, with dual mechanisms of action: (1) Aggresome-mediated proteostatic crisis: V8 immobilizes VCP, triggers protein aggregates in the cytoplasm and mitochondria, and induces mitochondrial injury; (2) Disruption of Mitophagy flux: VCP inhibition-induced damaged mitochondria recruit Mitophagy receptors (BNIP3/p62/TAX1BP1) to initiate Mitophagy, and VCP directly interacts with PRKN to promote Mitophagy initiation. However, V8 concurrently impairs lysosomal integrity, thereby obstructing Mitophagy flux and ultimately leading to GBM cell death. Additionally, VCP was found to not only maintain mitochondrial proteostasis but also preserve lysosomal integrity to facilitate the clearance of damaged mitochondria via Mitophagy.

Conclusion: Targeting VCP with inhibitors such as V8 induces mitochondrial dysfunction, effectively suppresses GBM cell viability, and holds potential for GBM therapy. VCP may serve as a promising therapeutic target for GBM.

Supplementary information: The online version contains supplementary material available at 10.1007/s13402-025-01149-3.

Keywords

Aggregates; Autolysosome; Mitophagy; PRKN; VCP.

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