Multi-omics analysis revealed the novel role of NQO1 in microenvironment, prognosis and immunotherapy of hepatocellular carcinoma.

NAD(P)H dehydrogenase quinone 1 (NQO1) is overexpressed in various cancers and is strongly associated with an immunosuppressive microenvironment and poor prognosis. In this study, we explored the role of NQO1 in the microenvironment, prognosis and immunotherapy of Hepatocellular carcinoma (HCC) using multi-omics analysis and machine learning. The results revealed that NQO1 was significantly overexpressed in HCC cells. NQO1(+)HCC cells were correlated with poor prognosis and facilitated tumor-associated macrophages (TAMs) polarization to M2 macrophages. We identified core NQO1-related genes (NRGs) and developed the NRGs-related risk-scores in hepatocellular carcinoma (NRSHC). The comprehensive nomogram integrating NRSHC, age, and pathological tumor-node-metastasis (pTNM) Stage achieved an area under the curve (AUC) above 0.7, demonstrating its accuracy in predicting survival outcomes and immunotherapy responses of HCC patients. High-risk patients exhibited worse prognoses but greater sensitivity to immunotherapy. Additionally, a web-based prediction tool was designed to enhance clinical utility. In conclusion, NQO1 may play a critical role in M2 polarization and accelerates HCC progression. The NRSHC model and accompanying tools offer valuable insights for personalized HCC treatment.