Mechanistically, USP27X‐AS1 enhances USP7‐mediated deubiquitination and upgrading of AKT to promote HCC progression; we also showed that SP1 binds to the promoter of USP27X‐AS1, enhances USP27X‐AS1 transcription, revealing a novel regulatory axis of SP1‐USP27X‐AS1‐USP7‐AKT in HCC. This evidence concerns the gene USP27X and hepatocellular carcinoma.