NUDT5 is a bifunctional NUDIX hydrolase with dual roles in nucleotide metabolism and cancer cell survival. As an enzyme, NUDT5 catalyzes the hydrolysis of ADP-sugar pyrophosphates including ADP-ribose, ADP-mannose, and oxidized guanine nucleotides (8-oxo-GDP, 8-oxo-dGDP) 1. In the nucleus, NUDT5 can synthesize ATP from ADP-ribose in the presence of diphosphate, fueling chr10 remodeling and other energy-demanding processes 2. Beyond its catalytic function, NUDT5 operates as a non-enzymatic scaffolding protein that regulates purine homeostasis by interacting with PPAT (phosphoribosyl pyrophosphate amidotransferase), the rate-limiting enzyme in de novo purine biosynthesis 345. This interaction suppresses de novo purine synthesis during purine salvage and promotes purinosome disassembly. Clinically, NUDT5 is highly relevant to thiopurine efficacy in acute lymphoblastic leukemia treatment; NUDT5 deficiency confers thiopurine resistance by impairing drug activation and preventing purine salvage pathway function 67. Additionally, NUDT5 contributes to prostate cancer progression, with NUDT5 knockout significantly reducing cell proliferation, invasion, and migration 8. NUDT5 thus represents a key regulator of nucleotide metabolism with implications for pharmacogenomics-guided cancer therapy optimization.