乙肝病毒（HBV）导致肝细胞癌（HCC）发生发展的过程中，细胞能量代谢模式显著改变，但其发生机制和促癌作用尚不清楚。我们前期研究发现HBV整合与炎症致突变酶APOBEC3上调可促进HCC进化，且均与呼吸链基因突变有关。由此提出科学假设：HBV导致的APOBEC3上调和HBV整合增加了线粒体基因突变水平，导致呼吸链功能异常并促进HCC发生发展。拟使用深度测序、体外实验、动物模型及分子流行病学的研究手段，阐明HBV整合与APOBEC3损伤呼吸链基因、导致氧化呼吸异常的机制，确定呼吸链功能异常状态下的替代性能量代谢模式和关键信号通路改变，明确其促进HCC适应生存选择压力进而发生发展的作用。利用已有的HBV感染者样本及HCC预后队列资源，评估机制研究中发现的节点分子对HCC发生风险和手术预后的预测作用。研究有望发现新的HBV促癌机制和生物标志物，为进一步完善HCC的防控和治疗措施提供理论依据。

During the process of hepatitis B virus (HBV) induced development of hepatocellular carcinoma (HCC), the energy metabolism of cells was significantly changed. The mechanism of metabolism reprogram is elusive, as well as its effect on carcinogenesis. Our previous studies found that, HBV integration and the elevated APOBEC3, an inflammatory mutagenic enzyme, can promote the evolution of HCC and they were both related with the generation of mutations in genes of respiratory chain. Therefore, a scientific hypothesis is proposed: HBV induced APOBEC3 elevation and HBV integration increase the mutation level of mitochondrial genes, that can lead to the dysfunction of respiratory chain and promote the development of HCC. Deep sequencing, in vitro experiments, in vivo experiments, and molecular epidemiological studies will be sequentially applied in this study. The project will firstly investigate the mechanism by which HBV integration and APOBEC3 injury the genes of respiratory chain and induce the abnormal aerobic respiration. Then, we will identify the compensatory pattern of energy metabolism and the altered signaling pathways under the condition of abnormal respiratory chain. Furthermore, it is going to investigate the effects of metabolism reprogram and altered signaling pathway on the adaptation and development of HCC under the survival selective pressure. Key molecular will be discovered as novel biomarkers during the mechanism study. The established sample database of HBV-infected subjects and HCC cohorts will be used to evaluate the value of novel biomarkers for predicting the risk of HCC and the postoperative prognosis. This project is hopeful for discovering a novel mechanism underlying the HBV induced hepatocarcinogenesis, as well as finding new biomarkers. Therefore, this project can provide a theoretical basis for improving the prevention and therapy strategy of HCC.