ACSS1 (acyl-CoA synthetase short chain family member 1) is a mitochondrial enzyme that catalyzes acetyl-CoA synthesis from acetate, with acetate as the preferred substrate 1. The enzyme plays critical roles across multiple physiological contexts. In metabolic homeostasis, ACSS1 mediates acetate utilization to support glycolysis and the tricarboxylic acid cycle. During sleep disruption, elevated hypothalamic acetate levels via ACSS1-dependent metabolism mitigate cognitive and metabolic impairments by activating pyruvate carboxylase 2. ACSS1 activity is regulated through sirtuin 3-mediated deacetylation at lysine 635, with acetylation-mimicking mutations impairing metabolism and promoting nonalcoholic fatty liver disease 3. ACSS1 expression inversely correlates with muscle mass in sarcopenia models 4. In cancer, ACSS1-dependent acetate metabolism rewires mitochondrial function to support acute myeloid leukemia and melanoma growth by decreasing glucose/glutamine contributions to the TCA cycle 5. In breast cancer, ACSS1 overexpression drives radioresistance by expanding the nuclear acetyl-CoA pool, enabling histone acetylation at DNA damage sites and facilitating homologous recombination repair 6. Acetate also functions as an epigenetic metabolite, with ACSS1/2-generated acetyl-CoA increasing histone H3 acetylation to activate lipogenic genes under hypoxia 7. These findings establish ACSS1 as a metabolic hub integrating energy production, epigenetic regulation, and disease pathogenesis.