NAE1 protein: a prognostic, immunomodulatory, and therapeutic biomarker associated with neddylation in hepatocellular carcinoma

Current predictive biomarkers for clinical outcomes and treatment in hepatocellular carcinoma (HCC) are not reliable enough. Neddylation, a novel post-translational modification, plays a crucial role in the immunomodulation, metabolism, and pathogenesis of HCC. However, whether it can function as a powerful predictive biomarker for HCC remains unknown. In current research, we first identified NAE1 as the most significant neddylation-related gene affecting the prognosis of HCC patients mainly through weighted gene co-expression network (WGCNA) and machine learning. Subsequently, we determined NAE1 expression as an independent risk factor for HCC using univariate and multivariate Cox regression and constructed a nomogram integrating NAE1 expression with clinical characteristics to predict survival probabilities in HCC patients. Bulk and single-cell RNA sequencing analyses revealed that NAE1 expression was primarily positively connected with immune cell infiltration in HCC, as assessed by the six latest immune algorithms. In addition, drug sensitivity and molecular docking collectively revealed the influence of NAE1 expression on the IC50 values of the four agents and the binding interactions between NAE1 protein and these drugs. Furthermore, we found that NAE1 depletion suppressed proliferation, migration, and invasion of HCC cells in vitro experiments. In conclusion, NAE1 protein holds considerable potential as a valuable biomarker for predicting clinical outcomes, immune landscapes, and drug sensitivity in HCC, as well as a promising therapeutic target.