While <i>CDKN2A</i> loss is classically associated with cell cycle deregulation through the p16-Cdk4-Rb axis, our findings suggest an additional layer of metabolic vulnerability arising from altered NAD<sup>+</sup> homeostasis in <i>CDKN2A</i>-deleted glioblastoma, revealing a metabolic-genetic interface for rationally revisiting NAD<sup>+</sup> targeting strategies, moving beyond the broad inhibition approaches. Here, CDKN2A is linked to glioblastoma.