HERC5-HSP60 ISGylation Axis Sustains Mitochondrial Homeostasis in Glioblastoma Stem Cells to Promote Tumor Progression

Glioblastoma (GBM), the most aggressive primary central nervous system (CNS) malignancy, exhibits rapid progression, therapy resistance, and inevitable recurrence—hallmarks primarily driven by glioblastoma stem cells (GSCs). Within the tumor microenvironment, dynamic crosstalk between GSCs and cytokines creates a niche for GSC maintenance. While interferon-gamma (IFN-γ) plays a well-established role in antitumor immunity, we reveal its paradoxical function in promoting the proliferation and self-renewal of GSCs. In this study, we show that IFN-γ induces the expression of HECT and RLD domain-containing E3 ubiquitin ligase 5 (HERC5) in GSCs, which functions as an ISG15 E3 ligase. HERC5 promotes mitochondrial stability by mediating the ISGylation of heat shock protein 60 (HSP60), a key mitochondrial chaperone. Genetic depletion of HERC5 leads to HSP60 degradation, mitochondrial dysfunction, and marked suppression of tumor growth, significantly prolonging survival in orthotopic GBM mouse models. These findings identify the HERC5–HSP60 axis as a critical mediator of GSC adaptation to cytokine-induced stress, highlighting HERC5 as a potential therapeutic target to disrupt GSC-driven tumorigenesis.