ATP Citrate Lyase, a critical enzyme that inhibits cancer metabolic reprogramming, induces ERS in HCC cells and promotes apoptosis of HCC cells by activating the P-EIF2α/ATF4/CHOP axis (Zheng et al., 2021) Both PI3K inhibitors and melatonin can increase the expression of CHOP in HCC cells and inhibit the PI3K/Akt pathway to reverse ERS-induced adriamycin resistance (Fan et al., 2013). The gene discussed is ATF4; the disease is hepatocellular carcinoma.