HINT2 (histidine triad nucleotide-binding protein 2) is a mitochondrial protein that serves as a key regulator of cellular energy metabolism and mitochondrial function. HINT2 exhibits adenosine 5'-monophosphoramidase activity, hydrolyzing purine nucleotide phosphoramidates to yield AMP and NH2 1. The protein functions as a critical regulator of mitochondrial oxidative phosphorylation (OXPHOS), interacting with cytochrome C oxidase II (MTCO2) to promote ATP production and reduce ROS accumulation 2. HINT2 enhances NAD+-dependent SIRT3 activation by promoting mitochondrial NAD+ influx through SLC25A51, thereby regulating mitochondrial protein acetylation 3. The protein also modulates mitochondrial calcium homeostasis through interactions with the mitochondrial calcium uniporter complex via MICU1 4. HINT2 expression is downregulated in multiple pathological conditions including metabolic dysfunction-associated steatotic liver disease (MASLD), acute pancreatitis, diabetic nephropathy, and colorectal cancer 3256. Loss of HINT2 function results in impaired mitochondrial bioenergetics, increased oxidative stress, enhanced inflammatory responses, and promotion of disease progression 74. These findings establish HINT2 as a potential therapeutic target for metabolic and inflammatory diseases.