<p>The Neddylation pathway is excessively activated in the occurrence and development of various cancers. However, there is currently a lack of comprehensive analysis of the Neddylation pathway in hepatocellular carcinoma (HCC). We treated HCC cells with a Neddylation pathway inhibitor (MLN4924) to observe its effects on the biological functions of HCC cells. Additionally, we constructed a Neddylation-related risk score (NRS) in HCC. Subsequently, we assessed the clinical value of NRS in predicting the prognosis of HCC and the efficacy of immunotherapy. Finally, we investigated the role of Proteasome 26S Subunit, Non-ATPase 1 (PSMD1) in the malignant progression of HCC through in vivo and in vitro experiments. MLN4924 significantly inhibits the proliferation and migratory capacity of HCC cells, promotes apoptosis, and upregulates PD-L1 expression. Moreover, we have confirmed through in vivo and in vitro experiments that MLN4924 can enhance the sensitivity to Sorafenib. Additionally, we found that patients in the high NRS group have poor prognoses and are prone to developing resistance to treatments such as Sorafenib and Oxaliplatin, while being more sensitive to 5-Fluorouracil and immunotherapy. Finally, in both in vitro and in vivo experiments, it was found that knocking down PSMD1 can weaken the proliferation and metastatic capacity of HCC cells. Furthermore, knocking down PSMD1 can inhibit the levels of PD-L1 protein and NEDD8 protein that binds to Cullin in HCC cells. Mechanistically, we found that PSMD1 stabilizes the protein expression of β-catenin by inhibiting its degradation through the ubiquitin–proteasome system, thereby influencing the expression of PD-L1. In conclusion, this study reveals that Neddylation-related characteristics can effectively predict the prognosis and immunotherapy outcomes of HCC. Furthermore, targeting PSMD1 may represent a potential therapeutic approach for HCC.</p>