SOCS3 suppresses glioblastoma growth via JAK-STAT inhibition and mitochondrial unfolded protein response activation

Glioblastoma (GBM) represents one of the most aggressive brain malignancies, characterized by rapid proliferation and pronounced resistance to apoptosis, resulting in poor therapeutic outcomes. Suppressor of cytokine signaling 3 (SOCS3), a crucial negative regulator of the JAK-STAT pathway, frequently undergoes epigenetic silencing in GBM. However, the tumor-suppressive functions of SOCS3 remain inadequately defined. The present study explores the role of SOCS3 in regulating mitochondrial stress responses and evaluates its therapeutic potential in GBM.

SOCS3 was overexpressed in GBM cell lines, and its effects on cell viability and apoptosis were assessed using MTT assays, TUNEL staining, and Western blotting. Proteomic profiling was performed to identify SOCS3-regulated pathways. A xenograft mouse model was used to validate tumor-suppressive effects in vivo. The impact of IL-6 (JAK-STAT activator) and Nicotinamide Riboside (NR, a mitochondrial stress inducer) was also examined.

SOCS3 overexpression significantly suppressed GBM cell proliferation and induced apoptosis. Proteomic analysis revealed upregulation of mitochondrial unfolded protein response (UPRmt) and mitophagy-related proteins. In vivo, SOCS3 reduced tumor growth and enhanced apoptotic signaling. IL-6 treatment restored JAK-STAT activity and reversed SOCS3-mediated tumor suppression. In contrast, NR treatment synergistically augmented SOCS3-induced mitochondrial stress and apoptosis, suggesting that mitochondrial dysfunction contributes to enhanced cell death.

SOCS3 exerts dual tumor-suppressive effects in GBM by inhibiting JAK-STAT signaling and activating mitochondrial stress pathways. These findings provide mechanistic insights into the function of SOCS3 and support its potential as a therapeutic target in GBM by promoting UPRmt-driven apoptosis.