Ceramide Stress Defines a Targetable Metabolic Vulnerability in IDH1-Mutant Oligodendroglioma

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.