An NAD ⁺ -dependent transcriptional program governs self-renewal and radiation resistance in glioblastoma

Significance Glioblastoma, the most common primary malignant brain tumor in adults, remains challenging despite multimodality therapy, necessitating the discovery of new therapies. Nicotinamide adenine dinucleotide (NAD + ) plays a pivotal role in cancer cell metabolism, but how NAD + impacts functional signaling events in glioblastoma is not well understood. We provide clinical evidence that high expression of NAMPT, the rate-limiting step in NAD + biosynthesis, in glioblastoma tumors is associated with poor overall survival in patients, and demonstrate NAMPT and NAD + are required for the maintenance of patient-derived glioblastoma stem-like cells (GSCs). Moreover, we delineate a NAD + -dependent transcriptional program that governs GSC self-renewal and dictates the radiation resistance of these cells. These findings identify potential new therapeutic avenues for the treatment of glioblastoma.