Histone deacetylases (HDACs) are responsible for catalyzing the deacetylation of histones, which closely related to many biological processes such as cell proliferation, differentiation and apoptosis. In recent years, HDAC inhibitors (HADCIs), with the anti-tumor potential, have been hot-spots of drug screening. Although the latest studies suggested that HDAC2 might influence the metabolism, the mechanism of HDACIs in metabolic regulation is still unclear. Here, we integrated the gene expression profiling of HDACIs (TSA and SAHA) in hepatocellular carcinoma cell (HepG2). The results showed 380 differentially expressed genes (DEGs) and 35 KEGG pathways enriched by DEGs in TSA-treatment group. Most of DEGs (177/380) and KEGG pathways (23/35) from TSA-treatment groups were confirmed by SAHA-treatment. About half of KEGG pathways (9/23) were related to metabolism ,and nearly one third of common DEGs (66/177) were involved in metabolic process. Moreover, HDAC2 siRNA experiment verified the effect of HDACIs on metabolic genes, suggesting that HDACIs potentially present a practical value to prevent tumor and other metabolism-related diseases.