Besides the conventional carbon sources,acetyl-CoA has recently been shown to begenerated from acetate in various types of cancers,where it promotes lipid synthesis andtumour growth.The underlying mechanism,however,remains largely unknown.We find thatacetate induces a hyperacetylated state of histone H3 in hypoxic cells.Acetate predominatelyactivateslipogenic genes ACACA and FASN expression by increasing H3K9,H3K27 andH3K56 acetylation levels at their promoter regions,thus enhancing de novo lipid synthesis,which combines with its function as the metabolic precursor for fatty acid synthesis.Acetyl-CoA synthetases(ACSS1,ACSS2)are involved in this acetate-mediated epigeneticregulation.More importantly,human hepatocellular carcinoma with high ACSS1/2 expressionexhibit increased histone H3 acetylation and FASN expression.Taken together,this studydemonstrates that acetate,in addition to its ability to induce fatty acid synthesis as animmediate metabolic precursor,also functions as an epigenetic metabolite to promote cancercell survival under hypoxic stress.