SQOR regulates H2S detoxification and lipid metabolism to maintain glioblastoma metabolic fitness.

Glioblastoma (GBM) adapts to metabolic stress through mitochondrial pathways that are not fully defined. Here, we show sulfide quinone oxidoreductase (SQOR) is upregulated in human GBM and functions as a mitochondrial checkpoint linking hydrogen sulfide (H 2 S) clearance to electron transport chain activity. In patient-derived GBM cells and immunocompetent syngeneic tumors, SQOR channels H 2 S-derived electrons into the ubiquinone pool to sustain oxidative phosphorylation during stress. Genetic or pharmacologic SQOR inhibition causes intracellular H 2 S accumulation, collapse of mitochondrial respiration, tricarboxylic acid cycle dysfunction, and compensatory glycolytic engagement. SQOR loss also redirects carbon into lipid synthesis and storage while impairing lipid mobilization, thereby limiting metabolic flexibility and stem-like cell maintenance. Increasing endogenous H 2 S production further exacerbates the bioenergetic defects caused by SQOR blockade. Functionally, genetic or pharmacologic SQOR inhibition suppresses tumor growth and prolongs survival in vivo . Together, these data identify SQOR-dependent sulfide oxidation as a mitochondrial liability that supports GBM metabolic plasticity.