Abstract Background Hepatocellular carcinoma (HCC) continues to pose a significant threat to patient survival. Emerging evidence underscores the pivotal involvement of long non‐coding RNAs (lncRNAs) in the cancer process. Nevertheless, our understanding of the roles and processes of lncRNAs in HCC remains limited. Methods The expression level of USP27X‐AS1 was assessed in an HCC patient cohort through a combination of bioinformatics analysis and qRT‐PCR. Subsequent biological experiments were conducted to delve into the functional aspects of USP27X‐AS1. Additional molecular biology techniques, including RNA pulldown and RNA immunoprecipitation (RIP), were employed to elucidate the potential mechanisms involving USP27X‐AS1 in HCC. Finally, CUT–RUN assay and other investigations were carried out to determine the factors contributing to the heightened expression of USP27X‐AS1 in HCC. Results High expression of the novel oncogene USP27X‐AS1 predicted poor prognosis in HCC patients. Further investigation confirmed that USP27X‐AS1 promoted the proliferation and metastasis of HCC by enabling USP7 to interact with AKT, which reduced level of AKT poly‐ubiquitylation and enhanced AKT protein stability, which improves protein stabilisation of AKT and promotes the progression of HCC. Moreover, we also revealed that SP1 binds to USP27X‐AS1 promoter to activate its transcription. Conclusions Novel oncogenic lncRNA USP27X‐AS1 promoted HCC progression via recruiting USP7 to deubiquitinate AKT. SP1 transcriptionally activated USP27X‐AS1 expression. These findings shed light on HCC and pointed to USP27X‐AS1 as a potential predictive biomarker and treatment target for the malignancy.
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