NAPRT catalyzes the first step in NAD biosynthesis via the Preiss-Handler pathway, converting nicotinic acid and 5-phospho-D-ribose 1-phosphate to beta-nicotinate D-ribonucleotide in an ATP-dependent reaction, thereby helping prevent cellular oxidative stress. NAPRT expression varies substantially across tissues and tumors, with emerging evidence that this variability determines therapeutic efficacy in cancer treatment. In multiple myeloma cells, NAPRT confers resistance to NAD-depleting agents by maintaining alternative NAD synthesis; NAPRT-knockout cells show weakened antioxidant defenses and increased genomic instability 1. Similarly, PPM1D mutations in pediatric gliomas silence NAPRT expression through CpG island hypermethylation, creating sensitivity to NAMPT inhibitors 2, and FH-deficient renal cell carcinomas exhibit NAPRT silencing via promoter hypermethylation, rendering them vulnerable to NAMPT inhibitors and PARP inhibitors 3. Recent structural studies have identified new NAPRT inhibitors that synergize with NAMPT inhibitors to deplete intracellular NAD and reduce cell viability 4. Dual NAMPT and NAPRT inhibition is emerging as a promising strategy in clinical trials for transplant-eligible multiple myeloma patients, and NAMPT-targeting PROTACs combined with nicotinic acid show robust efficacy in NAPRT-deficient cancers 5. Beyond oncology, NAPRT modulation influences cardiomyocyte ferroptosis 6 and neuronal differentiation 7.