In conclusion, the present study reveal that ACLY may represent a promising target in which its inhibition BMS‐303141 can induce ER stress and activate p‐eIF2α/ATF4/CHOP axis to promote apoptosis of HCC cells, and enhance the efficacy of HCC treatment through synergy with sorafenib. The gene discussed is EIF2A; the disease is hepatocellular carcinoma.