NAT8L catalyzes the synthesis of N-acetylaspartate (NAA) from L-aspartate and acetyl-CoA, a metabolite enriched in the central nervous system. Beyond its established role in brain metabolism, NAT8L has emerged as a key regulator in diverse pathological contexts. In cancer, NAT8L expression correlates with worse overall survival across multiple tumor types including ovarian, melanoma, renal cell, breast, colon, and uterine cancers 1. Mechanistically, NAT8L promotes tumor growth by sustaining aspartate availability for nucleotide biosynthesis and the pentose phosphate pathway 2. Additionally, tumors exploit NAT8L and NAA to suppress anti-tumor immunity by impairing natural killer and CD8+ T cell cytotoxicity through effects on immunological synapse formation, mimicking the anti-inflammatory properties of the healthy brain 3. In neurological disease, NAT8L appears neuroprotective: hippocampal overexpression of Shati/Nat8l improved cognitive outcomes in Alzheimer's disease models 4, while NAT8L mRNA oxidation in multiple sclerosis neurons impairs translation and reduces NAA synthesis, compromising myelin integrity 5. In psychiatric contexts, dorsal striatal NAT8L overexpression induces depression-like behaviors through metabotropic glutamate receptor 3 signaling 6. These findings identify NAT8L as a contextually important metabolic hub with potential therapeutic implications: NAT8L inhibition may enhance efficacy of cancer immunotherapies like trastuzumab and anti-PD-L1 antibodies, while modulation might address neurological and psychiatric disorders.