Abstract B014: SYNCRIP drives therapy resistance via ferroptosis suppression and metabolic activation in Glioblastoma

Abstract Synaptotagmin-binding Cytoplasmic RNA-Interacting Protein (SYNCRIP) is an RNA-binding protein (RBP) implicated in multiple cancers. Here, we report that SYNCRIP is significantly upregulated in glioblastoma (GBM) and correlates with poor prognosis and tumor progression. Mechanistically, SYNCRIP promotes SIRT1 expression at both transcriptional and post-transcriptional levels by stabilizing SIRT1 mRNA. Loss of SYNCRIP decreases SIRT1, increases ROS levels, and induces ferroptosis, which is reversed by SIRT1 restoration. Additionally, SYNCRIP enhances hexokinase 2 (HK2) expression via transcriptional activation and IRES-mediated translation, thereby promoting glycolysis. SYNCRIP depletion impairs mitochondrial function, cell migration, and invasion, partly through the downregulation of EMT-related factors. Collectively, these findings identify SYNCRIP as a key regulator of ferroptosis resistance and metabolic reprogramming in GBM, supporting its potential as a therapeutic target in glioblastoma. Citation Format: Hyeon Ji Kim, Hyo-Jin Song, Bo Kyung Joo, Jun-Nyeong Kim. SYNCRIP drives therapy resistance via ferroptosis suppression and metabolic activation in Glioblastoma [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Mechanisms of Cancer Immunity and Cancer-related Autoimmunity; 2025 Sep 24-27; Montreal, QC, Canada. Philadelphia (PA): AACR; Cancer Immunol Res 2025;13(9 Suppl):Abstract nr B014.