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The present study examins the anti\u2010tumor effects of deubiquitylating enzymes (DUB) inhibitors in HCC. It is found that the inhibitor of ubiquitin specific peptidase 8 (USP8) and DUB\u2010IN\u20103 shows the most effective anti\u2010cancer responses. Targeting USP8 inhibits the proliferation of HCC and induces cell ferroptosis. In vivo xenograft and metastasis experiments indicate that inhibition of USP8 suppresses tumor growth and lung metastasis. DUB\u2010IN\u20103 treatment or USP8 depletion decrease intracellular cystine levels and glutathione biosynthesis while increasing the accumulation of reactive oxygen species (ROS). Mechanistical studies reveal that USP8 stabilizes O\u2010GlcNAc transferase (OGT) via inhibiting K48\u2010specific poly\u2010ubiquitination process on OGT protein at K117 site, and STE20\u2010like kinase (SLK)\u2010mediated S716 phosphorylation of USP8 is required for the interaction with OGT. Most importantly, OGT O\u2010GlcNAcylates solute carrier family 7, member 11 (SLC7A11) at Ser26 in HCC cells, which is essential for SLC7A11 to import the cystine from the extracellular environment. 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