AACS (acetoacetyl-CoA synthetase) is a cytosolic enzyme that converts acetoacetate to acetoacetyl-CoA, functioning as a ketone body-utilizing enzyme critical for lipid biosynthesis 1. As part of a hierarchical hepatic de novo lipogenesis (DNL) substrate supply network, AACS provides an alternative pathway for cytosolic acetyl-CoA production when major lipogenic pathways are compromised; notably, CiC knockout increases acetoacetate-supplied hepatic acetyl-CoA production and DNL via AACS, indicating ketones function as reciprocal DNL precursors to mitochondrial citrate 1. Beyond canonical hepatic lipogenesis, AACS enables non-canonical β-hydroxybutyrate metabolism in cancer cells, generating cytosolic acetyl-CoA that bypasses the TCA cycle to support nucleotide, amino acid, and lipid synthesis for cell proliferation 2. Clinically, AACS expression is dysregulated in multiple disease contexts: in Parkinson's disease, AACS mRNA is downregulated and identified as a lipid metabolism biomarker in patient tissues 3; in hepatocellular carcinoma, upregulated AACS correlates with shorter overall and relapse-free survival and associates with immune cell infiltration 4. Additionally, genetic variation near AACS is associated with insulin resistance in metabolic syndrome populations 5, suggesting a role in systemic metabolic regulation beyond local lipid synthesis.