TY  - EJOU
AU  - Hsueh, Wei-Ting 
AU  - Chang, Kwang-Yu 
AU  - Tsai, Chin-Chuan 
AU  - Chen, Kuan-Tso 
AU  - Tsai, Kuen-Jang 
AU  - Hong, Zi-Xuan 
AU  - Liu, Chan-Chuan 
AU  - Chu, Jui-Mei 
AU  - Qiu, Li-Ying 
AU  - Lan, Yu-Yan 
AU  - Chien, Chia-Hung 

TI  - Revealing the Roles of the SH3GLB1-Hydrogen Peroxide Axis in Glioblastoma Multiforme Cells
T2  - Oncology Research

PY  - 2026
VL  - 34
IS  - 2
SN  - 1555-3906

AB  -  <b>Objectives:</b> Glioblastoma (GBM) is a prevalent malignant brain tumor prone to drug resistance. We previously found a strong correlation between SH3 domain GRB2-like endophilin B1 (SH3GLB1) and superoxide dismutase 2 (SOD2), which converts O<sub>2</sub> to hydrogen peroxide (H<sub>2</sub>O<sub>2</sub>). Prior studies show that H<sub>2</sub>O<sub>2</sub> redox signaling is vital for physiological processes and can drive tumor progression. Therefore, we aim to define how H<sub>2</sub>O<sub>2</sub> signaling regulates SH3GLB1 and AKT (protein kinase B) pathways in GBM and to assess whether modulating H<sub>2</sub>O<sub>2</sub> reverses temozolomide (TMZ) resistance. <b>Methods:</b> We used cultured cells and pharmacological inhibitors and activators to confirm the significance of H<sub>2</sub>O<sub>2</sub> signaling. GBM cells were used to verify the role of H<sub>2</sub>O<sub>2</sub> signaling in cell state transitions and animal experiments identified optimal treatment strategies. <b>Results:</b> We found that SOD2 acts as an upstream regulator of SH3GLB1. When SOD inhibitors and TMZ were combined, cells showed reduced SH3GLB1 and autophagy levels. SH3GLB1 was found to be regulated by H<sub>2</sub>O<sub>2</sub> via AKT signaling using redox homeostasis-regulating experiments. Although treatment-induced changes in mitochondrial H<sub>2</sub>O<sub>2</sub> levels mirrored those in the cytosol, parental and resistant cells exhibited divergent fates, highlighting cell-fate plasticity. TMZ combined with a redox modulator reduced resistant tumor cell growth (about 2/3 reduction of tumor size; <i>p</i> &lt; 0.05) and suppressed SH3GLB1 and autophagy levels in animal models. The TMZ-induced increase in SH3GLB1 expression was reversed by HgCl<sub>2</sub>, which inhibited the aquaporin-9/AKT signaling. <b>Conclusion:</b> Overall, these findings underscore the importance of H<sub>2</sub>O<sub>2</sub>-SH3GLB1 signaling in GBM and may inform future therapeutic strategies for overcoming TMZ resistance.
KW  - SH3 domain GRB2-like endophilin B1; glioblastoma; H<sub>2</sub>O<sub>2</sub>; redox; mitochondria

DO  - 10.32604/or.2025.071258