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

作者：Miao Z, Gu W, Ren Y, Lu C, Cai W, Lu J, Bao Z, Zhou Y, Li R, Jin K, Chen C, Wang H, Xu L, Chen J · 发表于：Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 年份：2026 · DOI：10.1002/advs.77044 · 被引用次数：49 · 研究领域：MBOAT2、ferroptosis、glioblastoma、lactylation、ubiquitination

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.