Hint1, or Histidine Triad Nucleotide-Binding Protein 1, is a nucleoside phosphoramidase with widespread expression [7]. It participates in multiple biological processes, regulating transcription, cell-cycle control, and may be involved in neuropsychiatric pathophysiology [2,3]. It also interacts with multiple G-protein-coupled receptors and transcription factors, playing roles as a regulator of CNS functions, a tumor suppressor, and a mast cell activator [7].

In cardiac hypertrophy, Hint1 was found to be downregulated in human hypertrophic heart samples. Hint1 knockout mice showed deteriorated cardiac hypertrophy after transverse aortic constriction, while cardiac-specific overexpression of Hint1 alleviated cardiac hypertrophy and dysfunction. Hint1 suppresses cardiac hypertrophy by inhibiting PKCβ1 membrane translocation and phosphorylation, attenuating the MEK/ERK/YY1 signal pathway, and downregulating HOXA5 expression [1]. In addition, Hint1-related autosomal recessive axonal neuropathy with neuromyotonia is associated with mutations in the Hint1 gene. Patients with such mutations often have early-onset neuropathy with neuromyotonia, and some may also present with neurodevelopmental or psychiatric features [2,4,5,6]. Hint1-deficient aged mice show reduced anxiety-like and depression-like behaviors and enhanced cognitive performance compared to age-matched wild-type mice [8].

In conclusion, Hint1 plays essential roles in the heart, nervous system, and in regulating emotions and cognition. Gene knockout mouse models have revealed its significance in cardiac hypertrophy, peripheral neuropathy, and neuropsychiatric-related phenotypes, providing insights into the mechanisms of these diseases and potential therapeutic targets.