Here, we report that SIRT4, which is up-regulated by α2δ1-mediated Ca2+ signaling, enhances the production of acetyl-CoA to promote the stemness and invasiveness of HCC by deacetylating MCCC2 at K269, which facilitates the complex formation with MCCC1, and thus enhances its MCCC enzymatic activity. Here, MCCC2 is linked to hepatocellular carcinoma.