原发性肝癌（HCC）占肝癌的80%，其中70%-80%的HCC是由乙型肝炎病毒（HBV）和丙型肝炎病毒（HCV）感染引起的慢性肝病。免疫治疗正在成为HCC治疗的支柱，然而令人注目的免疫介导的反应仅局限于个别患者。核酸感知（NAS）通路是先天免疫系统和抗病毒免疫反应的中心通路，但其在乙型肝炎病毒相关肝癌中的作用尚不明确。本研究基于多个公共数据集收集的乙型肝炎病毒相关HCC组织的转录组数据，进行了全面的生物信息学分析。根据与NAS相关的基因在病毒相关HCC患者中的表达，验证了两个亚群，称为NAS激活亚群和NAS抑制亚群。在此基础上，建立了一个NAS相关风险评分（NASRS）预测模型，用于乙型肝炎病毒相关HCC的风险分层和预后预测（TCGA-LIHC和ICGC队列）。在多个数据集中也验证了NASRS在预后和免疫治疗方面的预测价值。还建立了一个评估NASRS临床应用并通过不同途径展示其有效性的评分卡。此外，通过分子对接策略预测了与NAS标志物核心靶点结合的六种潜在药物。随后在体外和体内评估了潜在药物的细胞毒性能力。基于这些结果，我们得出结论：NASRS模型可以作为一种强大的预后生物标志物，并预测乙型肝炎病毒相关HCC患者对免疫治疗的反应，这在临床决策中对乙型肝炎病毒相关HCC患者具有重要意义。© 2023 Wiley Periodicals LLC.

Hepatocellular carcinoma (HCC) accounts for 80% of liver cancers, while 70%-80% of HCC developed from chronic liver disease with hepatitis B virus (HBV) and hepatitis C virus (HCV) infection as the major etiology. Immunotherapy is assuming a role as a pillar of HCC treatment, but the remarkable immune-mediated responses are restricted in a minority of patients. Nucleic acid sensing (NAS) pathways are the central pathway of the innate immune system and antiviral immune response to viral infection, but their role in hepatitis virus-related HCC remains undetermined. In our study, we performed a comprehensive bioinformatics analysis based on transcriptomic data of hepatitis virus related-HCC tissues collected from multiple public data sets. Two subgroups were validated based on NAS-related genes in virus-related HCC patients, which were defined as NAS-activated subgroups and NAS-suppressed subgroups based on the expression of NAS-related genes. On this basis, a NAS-related risk score (NASRS) predictive model was established for risk stratification and prognosis prediction in the hepatitis virus-related HCC (TCGA-LIHC and ICGC cohorts). The predictive values of the NASRS in prognosis and immunotherapy were also verified in multiple data sets. A nomogram was also established to facilitate the clinical use of NASRS and demonstrate its effectiveness through different approaches. Additionally, six potential drugs binding to the core target of the NAS signature were predicted via molecular docking strategy. We subsequently evaluated the cytotoxic capabilities of potential drug in vitro and in vivo. Based on these results, we conclude that the NASRS model could serve as a power prognostic biomarker and predict responses to immunotherapy, which is meaningful in clinical decision-making of hepatitis virus-related HCC patients.© 2023 Wiley Periodicals LLC.