Acetyl-CoA Acetyltransferase 1 (ACAT1) Depletion Promotes Hepatocellular Carcinoma (HCC) Migration and Invasion via Glycolysis-Driven Epigenetic Induction of Epithelial-Mesenchymal Transition (EMT)

Abstract

Acetyl-CoA acetyltransferase 1 (ACAT1), also known as mitochondrial acetoacetyl-CoA thiolase, is a mitochondrial enzyme that catalyzes the reversible interconversion between acetyl-CoA and acetoacetyl-CoA and is classically implicated in ketogenesis and ketolysis. Emerging evidence suggests that ACAT1 may serve as a diagnostic or prognostic biomarker in several malignancies, including kidney, prostate, and breast cancers. However, its clinical relevance and mechanistic contribution to hepatocellular carcinoma (HCC) progression have not been clearly elucidated. In this study, I investigated the biological role of ACAT1 in HCC progression. I demonstrate that reduced ACAT1 expression is significantly associated with unfavorable clinical outcomes in HCC patients. Through integrated transcriptomic, metabolomic, and functional analyses, I show that ACAT1 depletion reprograms glucose metabolic flux, leading to enhanced glycolytic activity and reduced engagement of the tricarboxylic acid (TCA) cycle. These metabolic alterations are accompanied by a global increase in protein acetylation, including a pronounced elevation in histone H3 lysine 9 acetylation (H3K9ac). I further demonstrate that this epigenetic reprogramming enhances the migratory and invasive potential of HCC cells and that these phenotypes can be modulated by pharmacological regulators of histone acetylation. Mechanistically, I identify the transcription factors TWIST2 and ZEB1 as critical downstream effectors that mediate ACAT1-dependent migration and invasion. Collectively, these findings indicate that ACAT1 depletion reprograms glucose metabolism and reshapes the epigenetic landscape, thereby enhancing the metastatic potential of HCC.