MCUB restricts mitochondrial calcium to support metabolic adaptation and homeostasis in glioblastoma

The refractory nature of glioblastoma (GBM) is largely attributed to metabolic plasticity and stress adaptation. However, the role of precise mitochondrial calcium ( m Ca 2+ ) flux gating in this context remains elusive. Here, we identify MCUB as a key gatekeeper upregulated in GBM, establishing a restricted m Ca 2+ threshold associated with malignancy. Mechanistically, MCUB limits m Ca 2+ uptake, attenuating pyruvate dehydrogenase activity and enforcing a glycolytic shift. MCUB deficiency triggers m Ca 2+ overload and reactive oxygen species bursts, sensitizing GBM cells to oxidative stress and radiotherapy. Moreover, hypoxia drives this adaptation via HIF-1α, which upregulates MCUB and reinforces its interaction with MCU to tune m Ca 2+ flux. Through high-throughput screening, we identify TF-PPAO as a compound interfering with the MCUB-MCU interaction. TF-PPAO exerts antitumor and radiosensitizing effects in xenografts, patient-derived xenografts (PDXs), and GBM organoids. Our findings reveal MCUB-mediated m Ca 2+ restriction as a mechanism of GBM metabolic adaptation and mitochondrial homeostasis, highlighting MCUB as a therapeutic target.