Compared to its limited effect in cell culture assays (Supplementary information, Fig. S6a), the observed robust phenotype of SMYD5 ablation in animal models could be explained by the constrained mTOR activity in vivo, due to limited nutrition and oxygen availability.40 Our study thus nominates SMYD5 as a novel therapeutic target for HCC, whose efficacy could be further enhanced in combination with mTOR suppression. Here, SMYD5 is linked to hepatocellular carcinoma.