NME2 is a multifunctional nucleoside diphosphate kinase (NDPK) encoded on chromosome 17, located within 18kb of the NME1 gene 1. Its primary catalytic function involves transferring the gamma-phosphoryl group from ATP to nucleoside diphosphates via a ping-pong mechanism with a phosphohistidine intermediate, maintaining nucleoside triphosphate homeostasis 2. Beyond nucleotide metabolism, NME2 functions as a protein histidine kinase, phosphorylating target proteins including KCNN4 at His-358 to activate calcium-dependent potassium channel activity in immune cells 3. NME2 also translocates to the nucleus where it binds single-stranded DNA and G-quadruplex structures in gene promoters, particularly the MYC oncogene, regulating transcription independently of its kinase function 4. In hepatocellular carcinoma (HCC), NME2 overexpression correlates with poor prognosis and promotes cell proliferation by phosphorylating 4EBP1 at Thr37/46 through an mTOR-independent pathway that modulates autophagy and translation initiation 5. Additionally, NME2 interacts with dynamin GTPases to facilitate receptor endocytosis, a mechanism linked to its metastasis suppressor function 6. Notably, NME2 expression in brain tissue shows detrimental effects on sarcopenia-related traits 7, and serves as a potential biomarker in hepatitis B-associated HCC 8.