This study was designed to test the hypothesis that ACLY can promote the proliferation, migration and invasion of HCC, while its inhibitor BMS‐303141 alleviates this effect by triggering ER stress through activation of p‐eIF2α/ATF4/CHOP axis; moreover, ACLY in combination with sorafenib can improve the efficacy of HCC therapy. The gene discussed is ATF4; the disease is hepatocellular carcinoma.