SIRT3 Regulates HMGCS2 Deacetylation and Influences Cholangiocarcinoma Progression via the Metabolism of Ketone Bodies

This laboratory study examined HMGCS2, a mitochondrial ketogenesis enzyme, in cholangiocarcinoma using TCGA data, immunoblotting, two cell lines (HuCCT-1 and RBE), an in vivo xenograft model, metabolomics and clinical samples. HMGCS2 was downregulated in cholangiocarcinoma, overexpression inhibited proliferation and invasion, and knockdown promoted them, in vitro and in vivo. Metabolomics showed HMGCS2 enhanced ketone body synthesis, and exogenous ketone bodies mimicked its antitumor effects. SIRT3 deacetylated HMGCS2 at K310, and low HMGCS2 and SIRT3 expression correlated with poor patient survival.