In this study, using clinical patient samples, HCC cell culture models, xenograft model, especially the Mettl1 knockin and conditional knockout mouse models, we demonstrated strong evidence supporting the critical function of METTL1/WDR4‐mediated m7G tRNA modifications in promoting HCC tumourigenesis and progression in vitro and in vivo, highlighting the important physiological functions of overactive m7G tRNA modification in HCC. This evidence concerns the gene METTL1 and hepatocellular carcinoma.