HPRT1 (hypoxanthine phosphoribosyltransferase 1) is a purine salvage enzyme that catalyzes the conversion of guanine to guanosine monophosphate and hypoxanthine to inosine monophosphate by transferring the 5-phosphoribosyl group from 5-phosphoribosylpyrophosphate [UniProt]. This salvage pathway is essential for nucleotide homeostasis, particularly under metabolic stress conditions. When electron transport chain function is compromised, cells suppress de novo purine synthesis and enhance purine salvage through increased HPRT1 expression, driven by pentose phosphate pathway activation 1. In cancer contexts, HPRT1 plays multiple pro-tumorigenic roles: mutated EGFR upregulates HPRT1 via HIF-1α-mediated transcriptional activation to promote lung adenocarcinoma tumorigenesis and gefitinib resistance 2; HPRT1 catalyzes conversion of temozolomide metabolites to activate AMPK, driving glioblastoma chemoresistance 3; and HPRT1 upregulation correlates with poor prognosis and enhanced PD-1 expression in multiple cancer types 4. Conversely, HPRT1 deficiency causes Lesch-Nyhan syndrome, a severe X-linked neurogenetic disorder resulting from loss-of-function mutations 56. Emerging evidence suggests HPRT1 inhibition may sensitize cancer cells to standard therapies and that modulating HPRT1 activity could address metabolic imbalances in conditions like osteoporosis 7.