BACKGROUND In recent years, many studies have shown that proteasome 26S subunit non-ATPase 6 (PSMD6) plays an important role in the occurrence and development of malignant tumours. Unfortunately, there are no reports on the evaluation of the potential role of PSMD6 in hepatocellular carcinoma (HCC). AIM To comprehensively evaluate the overexpression pattern and clinical significance of PSMD6 in HCC tissues. METHODS This study integrated PSMD6 mRNA expression profiles from 4672 HCC and 3667 non-HCC tissues, along with immunohistochemical scores from 383 HCC and adjacent tissues, to assess PSMD6 overexpression in HCC. Clustered regularly interspaced short palindromic repeats knockout technology evaluated PSMD6’s essential role in HCC cell growth. Functional enrichment analysis explored the molecular mechanism of PSMD6 abnormalities in HCC. Drug sensitivity analysis and molecular docking analysed the effect of abnormal expression of PSMD6 on the drug sensitivity of HCC cells. RESULTS The results of 41 external and two internal datasets showed that PSMD6 mRNA (SMD = 0.26, 95%CI: 0.09-0.42, P < 0.05) and protein (SMD = 2.85, 95%CI: 1.19-4.50, P < 0.05) were significantly overexpressed in HCC tissues. The integrated analysis results showed that PSMD6 had a significant overexpression pattern in HCC tissues (SMD = 0.40, 95%CI: 0.15-0.66, P < 0.05). PSMD6 knockout inhibited HCC cell growth (chronos scores < -1). Functional enrichment implicated ribosome biogenesis and RNA splicing. Significant enrichment of signalling pathways such as RNA degradation, ribosomes, and chemical carcinogenesis—reactive oxygen species. Drug sensitivity analysis and a molecular docking model showed that high expression of PSMD6 was associated with the tolerance of HCC cells to drugs such as ML323, sepantronium bromide, and GDC0810. Overexpressed PSMD6 effectively distinguished HCC tissues (AUC = 0.75, 95%CI: 0.71-0.79). CONCLUSION This study was the first to discover that PSMD6 was overexpressed in HCC tissues. PSMD6 is essential for the growth of HCC cells and may be involved in ribosome biogenesis and RNA splicing.
