Mechanistically, targeting USP8 destabilized OGT via promoting K48‐specific poly‐ubiquitination process on OGT protein at K117 site, thus decreasing the Ser26 O‐GlcNAcylation of solute carrier family 7, member 11 (SLC7A11) in HCC cells, which is essential for SLC7A11 to import the cystine from the extracellular environment. This evidence concerns the gene SLC17A1 and hepatocellular carcinoma.