2199 - SIRT3-Mediated Radioresistance in Glioblastoma: A Systematic Review and Mechanistic Synthesis
Presenter(s)
L. Samhouri1, A. Aljbaly2, M. Ajo3, A. Haddad3, and A. Mohammad4; 1Department of Radiology, jordan university of science and technology, irbid, Jordan, 2Jordan University of Science and Technology., irbid, Jordan, 3jordan University of Science and Technology., Irbid, Jordan, 4Saudi Center for Radiotherapy, King Abdullah University Hospital, Irbid, Jordan
Purpose/Objective(s):
Glioblastoma (GBM) exhibits near-universal recurrence, with 80–90% of failures arising within the high-dose irradiated margin. This pattern suggests that resistance is not purely intrinsic but may involve radiation-induced adaptive survival programs. Sirtuin-3 (SIRT3), a mitochondrial NAD?-dependent deacetylase, regulates oxidative stress and metabolic fitness. We investigated whether ionizing radiation (IR) promotes a SIRT3-mediated mitochondrial defence axis that enhances glioma stem cell (GSC) survival and therapeutic escape.
Materials/Methods:
A structured mechanistic synthesis of preclinical GBM models (2000–2025) was conducted, integrating laboratory data with clinical bioinformatic validation. Study quality was appraised using established risk-of-bias tools. Clinical correlation was performed using the TCGA-GBM dataset (n=157), evaluating SIRT3 transcript levels against overall survival (OS) using Cox proportional hazards modelling and Kaplan–Meier analysis.
Results:
Evidence supports a cooperative two-step SIRT3 activation program following IR. First, radiation induces transcriptional upregulation of SIRT3 via NF-?B signalling. Second, Cyclin B1/CDK1 phosphorylates SIRT3 at Thr150/Ser159, enhancing its deacetylase activity. Activated SIRT3 deacetylates and stimulates MnSOD (SOD2), augmenting mitochondrial ROS detoxification and preserving mitochondrial integrity under radiation stress.
In GSCs, SIRT3 functionally interacts with TRAP1 to sustain oxidative phosphorylation capacity while limiting ROS accumulation, supporting stemness and metabolic plasticity. Additionally, SIRT3 modulates ferroptosis susceptibility through the ATF4–SLC7A11 axis, maintaining glutathione synthesis and suppressing lipid peroxidation.
Inhibition of SIRT3 (3-TYP or shRNA) or disruption of CDK1-mediated phosphorylation sensitized GBM models to radiation and increased ferroptotic vulnerability in vivo. TCGA analysis demonstrated that elevated SIRT3 expression was significantly associated with poorer OS (p=0.0322).
Conclusion:
These findings support a model in which radiation actively engages a SIRT3-dependent mitochondrial stress adaptation program rather than merely selecting for pre-existing resistant clones. Targeting the CDK1–SIRT3–MnSOD axis may represent a rational radiosensitization strategy by collapsing mitochondrial redox buffering and lowering the ferroptotic threshold. Disrupting this adaptive “mitochondrial shield” offers a translational opportunity to enhance radiation response in GBM.