Ceramide stress defines a targetable metabolic vulnerability in IDH1-mutant oligodendroglioma

Abstract Oligodendroglioma is genetically defined by mutations in isocitrate dehydrogenase 1 or 2 (IDH1/IDH2) and 1p/19q codeletion. These tumors exhibit a distinct metabolic state driven by the oncometabolite D-2-hydroxyglutarate, which shifts the sphingosine-1-phosphate–ceramide rheostat toward ceramide accumulation. Taking advantage of this intrinsic metabolic state, we investigated whether further elevating ceramide levels through inhibition of acid ceramidase—a key enzyme that degrades ceramide to sphingosine—could promote apoptotic cell death. Analysis of patient datasets demonstrated that acid ceramidase is expressed at higher levels in both low- and high-grade gliomas compared with normal tissue. Treatment with SABRAC, a small-molecule inhibitor of acid ceramidase, robustly reduced viability in IDH1-mutant oligodendroglioma cell lines and induced rapid, marked accumulation of multiple ceramide species with coordinated sphingolipid remodeling. Subcellular imaging using a fluorescent ceramide analogue revealed increased ceramide localization to lysosomes and mitochondria following SABRAC treatment. This was associated with cytochrome c redistribution, executioner caspase activation, and apoptotic cell death, consistent with engagement of the intrinsic mitochondrial pathway. Transcriptomic and biochemical analyses further demonstrated activation of endoplasmic reticulum stress and unfolded protein response signaling, including PERK- and IRE1α-associated programs, indicating a coordinated multi-organelle stress response to sustained ceramide elevation. These mechanistic effects translated into prolonged survival in oligodendroglioma xenograft-bearing mice. Together, these findings suggest that IDH1-mutant oligodendroglioma harbors a heightened sensitivity to ceramide stress and identify ceramide accumulation as a therapeutically actionable metabolic vulnerability.