CMPK2 is a mitochondrial nucleotide monophosphate kinase that catalyzes phosphorylation of pyrimidine monophosphates (dUMP, dCMP, CMP, UMP) to support mitochondrial DNA synthesis 1. The enzyme shows highest catalytic efficiency for dUMP, followed by dCMP [UniProt]. CMPK2-dependent mtDNA synthesis generates oxidized mtDNA fragments upon cellular stress, which activate the NLRP3 inflammasome complex 12. This mechanism links mitochondrial metabolism to innate immunity and represents a critical node in multiple inflammatory pathologies. CMPK2 is upregulated in macrophages during inflammatory challenges and plays pathogenic roles in diverse conditions. In ischemic stroke, microglial CMPK2 promotes neuroinflammation and brain injury through NLRP3 activation, with CMPK2 inhibition (using nordihydroguaiaretic acid) reducing infarct volume 1. In metabolic dysfunction-associated steatohepatitis (MASH), hepatocyte CMPK2 upregulation drives disease progression via mtDNA-NLRP3 signaling; genetic deletion or pharmacological inhibition suppresses fibrosis and pyroptosis 3. CMPK2 similarly mediates inflammation in allergic rhinitis 4, atherosclerosis 5, and rheumatoid arthritis 6 through mtDNA-STING pathway activation. Mutations in CMPK2 cause autosomal recessive basal ganglia calcification (Fahr's disease) 7. Therapeutically, CMPK2 inhibition emerges as a promising strategy for inflammatory and metabolic diseases.