In conclusion, treatment with C2-ceramide alone increases the protein level of CERS2, modulating sphingolipid metabolism to favor the conversion of C2-ceramide to a prosurvival sphingolipid and activating the UPR, including the PERK, IRE1α, and ATF6 pathways, to alleviate misfolded protein-induced stress in HCC cells. This evidence concerns the gene EIF2AK3 and hepatocellular carcinoma.