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

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.