HINT1 is a multifunctional protein with both enzymatic and scaffolding roles. It exhibits adenosine 5'-monophosphoramidase activity, hydrolyzing purine nucleotide phosphoramidates and related compounds, and possesses SUMO-specific isopeptidase activity that deconjugates SUMO1 from target proteins. Beyond its catalytic functions, HINT1 acts as a scaffolding protein that modulates transcriptional complexes involving LEF1/TCF1 and MITF, regulates p53-mediated apoptosis, and inhibits ubiquitin-mediated protein degradation. Recent studies reveal HINT1's roles in human disease. A high frequency of HINT1 mutations has been identified in people of Slavic origin presenting with neuromuscular hyperexcitability syndromes 1. In cardiovascular disease, HINT1 is upregulated in aortic aneurysm tissue and promotes vascular smooth muscle cell phenotypic switching through the ITGA6/FAK signaling axis; FAK inhibition by defactinib treatment limits aneurysm development 2. Conversely, HINT1 expression is reduced in hypertrophic hearts, and cardiac-specific HINT1 overexpression alleviates hypertrophy by suppressing HOXA5 expression and downstream TGF-β signaling 3. In inflammatory bowel disease, genetically predicted higher circulating HINT1 levels are inversely associated with overall IBD risk and Crohn's disease specifically 4. HINT1 also functions as a tumor suppressor in colon cancer by inhibiting AP-1 transcription factor activity through interaction with the POSH-JNK2 complex 5.