NUDT8 is a mitochondrial acyl-CoA diphosphatase that plays a critical role in coenzyme A (CoA) metabolism and metabolic-inflammatory crosstalk. Primary function: NUDT8 hydrolyzes a broad range of CoA and acyl-CoA substrates, preferring free CoA, hexanoyl-CoA, and octanoyl-CoA while showing minimal activity against acetyl-CoA 1. The enzyme exhibits a distinctive preference for manganese ions and resides specifically in mitochondria, enabling compartment-specific CoA pool regulation 1. Mechanism: Beyond CoA degradation, NUDT8 possesses decapping activity toward dpCoA-capped RNAs in vitro 2. Disease relevance: NUDT8 dysfunction has been implicated in osteoarthritis pathogenesis, where increased mitochondrial NUDT8 in osteocytes promotes cholesterol accumulation and CoA degradation, leading to cytosolic mtDNA accumulation and cGAS-STING pathway activation in chondrocytes 3. Additionally, NUDT8 is identified as a miR-483-5p target gene involved in oxidative stress regulation relevant to coronary artery disease 4. Clinical significance: Pharmacological targeting of osteocyte mitochondrial NUDT8 through pantethine supplementation ameliorates cartilage inflammation and joint pain in osteoarthritis models, suggesting therapeutic potential 3. The broad tissue distribution of NUDT8 indicates its importance across multiple metabolic contexts.