Metabolic Reprogramming in Glioblastoma Stem Cells Promotes Radiation Resistance Through a H3K18la/USP30/MBOAT2 Axis

ABSTRACT

Mesenchymal glioma stem cells (MES GSCs) are closely associated with glioblastoma radioresistance, yet the mechanisms linking MES‐state maintenance to ferroptosis resistance remain incompletely defined. Here, we show that MES GSCs exhibit enhanced glycolytic activity and lactate production, driven in part by MES‐associated transcriptional regulators that promote LDHA expression. LDHA‐derived lactate induces p300‐dependent H3K18 lactylation, which enhances USP30 transcription. USP30 subsequently stabilizes the lipid‐remodeling enzyme MBOAT2 by limiting its ubiquitination, leading to phosphatidylethanolamine remodeling toward ferroptosis‐resistant PE‐MUFA species. Disruption of this LDHA–H3K18la–USP30–MBOAT2 axis by LDHA inhibition, impaired H3K18 lactylation, USP30 inhibition, or MBOAT2 depletion increases lipid peroxidation, promotes ferroptosis, and sensitizes MES GSCs to irradiation. Lipid rescue experiments further identify PE‐MUFA remodeling as a functional mediator of MBOAT2‐dependent ferroptosis resistance. In intracranial xenografts, combined targeting of glycolysis and USP30 enhances radiotherapeutic efficacy without obvious treatment‐associated body weight loss under the tested conditions. These findings reveal a metabolic–epigenetic–lipid remodeling circuit that protects MES GSCs from ferroptosis and promotes radioresistance.