SYNCRIP drives ferroptosis resistance and metabolic activation via SIRT1 and HK2 in glioblastoma.

Synaptotagmin-binding cytoplasmic RNA-interacting protein (SYNCRIP) is an RNA-binding protein (RBP) implicated in the pathogenesis of various cancers through involvement in regulating multiple cellular processes. Notably, this study identified that SYNCRIP expression is significantly elevated in glioblastoma (GBM) and is associated with poor prognosis and tumor progression. Mechanistically, SYNCRIP upregulates SIRT1 expression at both the transcriptional and post-transcriptional levels by stabilizing SIRT1 mRNA. Meanwhile, loss of SYNCRIP leads to reduced SIRT1 expression, accumulation of reactive oxygen species (ROS), and induction of ferroptosis. Notably, restoration of SIRT1 rescues cells from ferroptotic cell death, supporting the critical role of SIRT1 in SYNCRIP-mediated ferroptosis resistance. SYNCRIP also enhances hexokinase 2 (HK2) expression through transcriptional activation and internal ribosome entry site (IRES)-mediated translation, thereby promoting glycolytic activity in GBM. Furthermore, depletion of SYNCRIP results in mitochondrial dysfunction and impairs GBM cell migration and invasion by downregulating epithelial-mesenchymal transition (EMT)-associated factors. Collectively, these findings suggest that SYNCRIP is a key regulator of GBM progression by maintaining metabolic homeostasis and ferroptosis resistance, highlighting SYNCRIP as a potential therapeutic target in GBM.