NME1-NME2 encodes nucleoside diphosphate kinase (NDPK) isoforms responsible for maintaining cellular (d)NTP pools 1. The readthrough product integrates functions of both NME1 and NME2, which show distinct subcellular localization and oligomerization patterns. Under normal conditions, both proteins co-localize in the cytoplasm but translocate to the nucleus upon DNA damage, where they may perform specific functions in homomeric states 1. Double knockout studies demonstrate that combined NME1-NME2 loss causes severe fetal lethality with profound anemia from impaired erythropoiesis, contrasting with viable single knockouts 2. NME1 possesses metastasis-suppressor functions, whereas NME2 regulates heterotrimeric G protein activation and ion channel function 2. Clinically, elevated NME1-NME2 expression associates with poor outcomes in lung adenocarcinoma with bone metastasis (HR=2.65, p=3.9E-15) 3 and is detected in medulloblastoma cerebrospinal fluid as a potential diagnostic biomarker 4. In Mendelian randomization analysis, amygdala-expressed NME1-NME2 showed detrimental effects on multiple sarcopenia-related traits through immune-related signaling mechanisms 5. Conversely, NME1-NME2 expression appears protective in controlled asthma, being exclusively detected in controlled asthmatics 6. These findings indicate context-dependent roles spanning DNA repair, cellular energy homeostasis, metastatic processes, and systemic immune regulation.