Metabolic Reprogramming in Glioblastoma Stem Cells Promotes Radiation Resistance Through a H3K18la/USP30/MBOAT2 Axis
Zong Miao1, Wei Gu2, Yimin Ren3
1Department of Neurosurgery, Changhai Hospital, Naval Medical University (Second Military Medical University), Shanghai, China.
Advanced Science (Weinheim, Baden-Wurttemberg, Germany)
|August 12, 2026
Summary
Mesenchymal glioma stem cells resist ferroptosis and radiation via a metabolic-epigenetic-lipid pathway. Targeting this axis, involving LDHA and USP30, sensitizes these cells, offering new glioblastoma treatment strategies.
Area of Science:
- Neuro-oncology
- Cancer Metabolism
- Epigenetics
Background:
- Mesenchymal glioma stem cells (MES GSCs) are linked to glioblastoma radioresistance.
- Mechanisms of MES GSC ferroptosis resistance are not fully understood.
Purpose of the Study:
- To elucidate the metabolic and epigenetic mechanisms underlying MES GSC ferroptosis resistance.
- To identify therapeutic targets to overcome glioblastoma radioresistance.
Main Methods:
- Analysis of glycolytic activity and lactate production in MES GSCs.
- Investigation of the role of LDHA, H3K18 lactylation, USP30, and MBOAT2 in ferroptosis resistance.
- Assessment of therapeutic interventions including LDHA inhibition, USP30 inhibition, and MBOAT2 depletion.
- Evaluation of combined targeting of glycolysis and USP30 in intracranial xenografts.
Main Results:
- MES GSCs show increased glycolysis and lactate production, promoting H3K18 lactylation and USP30 transcription.
- USP30 stabilizes MBOAT2, leading to ferroptosis-resistant lipid remodeling (PE-MUFA).
- Disrupting the LDHA-H3K18la-USP30-MBOAT2 axis increases lipid peroxidation, induces ferroptosis, and sensitizes MES GSCs to irradiation.
- Combined targeting of glycolysis and USP30 improved radiotherapeutic efficacy in vivo.
Conclusions:
- A novel metabolic-epigenetic-lipid remodeling circuit protects MES GSCs from ferroptosis and contributes to radioresistance.
- Targeting this circuit, particularly glycolysis and USP30, represents a promising strategy for glioblastoma treatment.
Related Concept Videos
02:56Treatment Resistant Cancers
Cancer is the second leading cause of death in the United States. A cancer cell is genetically unstable and hence can mutate faster. They can also modify their microenvironment and escape immune surveillance. The difficulties in treating cancer are further compounded by the emergence of rapid resistance to anticancer drugs. The most common ways to attain resistance in cancer cells include alteration in drug transport and metabolism, modification of drug target, elevated DNA damage response, or...
03:03mTOR Signaling and Cancer Progression
The mammalian target of rapamycin or mTOR protein was discovered in 1994 due to its direct interaction with rapamycin. The protein gets its name from a yeast homolog called TOR. The mTOR protein complex in mammalian cells plays a major role in balancing anabolic processes such as the synthesis of proteins, lipids, and nucleotides and catabolic processes, such as autophagy in response to environmental cues, such as availability of nutrients and growth factors.
The mTOR pathway or the...
The mTOR pathway or the...
01:24Methods of Nuclear Reprogramming
Nuclear reprogramming is a process of transforming one cell type into an unrelated cell type by epigenetic changes that alter the cell’s original gene expression pattern. Such epigenetic changes force cells to express a different set of genes, which play a significant role in inducing transformation into other cell types. Nuclear reprogramming offers applications in reproductive cloning for livestock propagation and regenerative medicine — developing patient-specific cells for injury repair.