The NUDIX hydrolase NUDT5 influences purine nucleotide metabolism and thiopurine pharmacology

Purine nucleotides are critical for nucleic acid synthesis, signaling, and cellular metabolism. Thiopurines (TPs), including 6-mercaptopurine and 6-thioguanine, are cornerstone agents for the treatment of acute lymphoblastic leukemia (ALL). TP efficacy and cytotoxicity depend on the metabolism and intracellular activation of TPs, a process influenced by pharmacogenes such as thiopurine-S methyltransferase (TPMT) and NUDIX (nucleoside diphosphates linked to moiety-X) hydrolase 15 (NUDT15). In this issue of the JCI, Maillard et al. identified NUDT5 as a determinant of TP pharmacology. They demonstrated that loss of NUDT5 conferred TP resistance by impairing drug activation and DNA damage responses. Metabolomics studies by Maillard and others revealed that NUDT5 may regulate the balance between the de novo purine synthesis and salvage pathways. Clinically, NUDT5 expression variants were associated with altered TP tolerance. These findings position NUDT5 as a key modulator of nucleotide metabolism and TP efficacy, with potential implications for pharmacogenomics-guided therapy optimization in ALL.