Liver cancer is the second most frequent cause of cancer-related death globally. The main histological subtype is hepatocellular carcinoma (HCC), which is derived from hepatocytes. According to the epidemiologic studies, the most important risk factors of HCC are chronic viral infections (HBV, HCV, and HIV) and metabolic disease (metabolic syndrome). Interestingly, these carcinogenic factors that contributed to HCC are associated with MDM2–p53 axis dysfunction, which presented with inactivation of p53 and overactivation of MDM2 (a transcriptional target and negative regulator of p53). Mechanically, the homeostasis of MDM2–p53 feedback loop plays an important role in controlling the initiation and progression of HCC, which has been found to be dysregulated in HCC tissues. To maintain long-term survival in hepatocytes, hepatitis viruses have lots of ways to destroy the defense strategies of hepatocytes by inducing TP53 mutation and silencing, promoting MDM2 overexpression, accelerating p53 degradation, and stabilizing MDM2. As a result, genetic instability, chronic ER stress, oxidative stress, energy metabolism switch, and abnormalities in antitumor genes can be induced, all of which might promote hepatocytes’ transformation into hepatoma cells. In addition, abnormal proliferative hepatocytes and precancerous cells cannot be killed, because of hepatitis viruses-mediated exhaustion of Kupffer cells and hepatic stellate cells (HSCs) and CD4⁺T cells by disrupting their MDM2–p53 axis. Moreover, inefficiency of hepatic immune response can be further aggravated when hepatitis viruses co-infected with HIV. Unlike with chronic viral infections, MDM2–p53 axis might play a dual role in glucolipid metabolism of hepatocytes, which presented with enhancing glucolipid catabolism, but promoting hepatocyte injury at the early and late stages of glucolipid metabolism disorder. Oxidative stress, fatty degeneration, and abnormal cell growth can be detected in hepatocytes that were suffering from glucolipid metabolism disorder, and all of which could contribute to HCC initiation. In this review, we focus on the current studies of the MDM2–p53 axis in HCC, and specifically discuss the impact of MDM2–p53 axis dysfunction by viral infection and metabolic disease in the transformation of normal hepatocytes into hepatoma cells. We also discuss the therapeutic avenues and potential targets that are being developed to normalize the MDM2–p53 axis in HCC.

肝癌是全球第二大癌症相关死亡原因。主要的组织学亚型是肝细胞癌（HCC），其源自肝细胞。根据流行病学研究，HCC最重要的危险因素是慢性病毒感染（HBV、HCV和HIV）和代谢性疾病（代谢综合征）。有趣的是，这些导致 HCC 的致癌因素与 MDM2-p53 轴功能障碍有关，表现为 p53 失活和 MDM2（p53 的转录靶标和负调节因子）过度激活。从机械角度来看，MDM2-p53 反馈环路的稳态在控制 HCC 的发生和进展中发挥着重要作用，并且已发现 HCC 组织中 HCC 失调。为了维持在肝细胞中的长期存活，肝炎病毒有很多方法来破坏肝细胞的防御策略，包括诱导TP53突变和沉默、促进MDM2过度表达、加速p53降解、稳定MDM2。结果，可以诱导遗传不稳定性、慢性内质网应激、氧化应激、能量代谢转换和抗肿瘤基因异常，所有这些都可能促进肝细胞转化为肝癌细胞。此外，异常增殖的肝细胞和癌前细胞无法被杀死，因为肝炎病毒介导的库普弗细胞、肝星状细胞 (HSC) 和 CD4 ⁺ T 细胞通过破坏其 MDM2-p53 轴而耗尽。此外，当肝炎病毒与艾滋病毒合并感染时，肝脏免疫反应的低效会进一步加剧。与慢性病毒感染不同，MDM2-p53轴可能在肝细胞糖脂代谢中发挥双重作用，表现为增强糖脂分解代谢，但在糖脂代谢紊乱的早期和晚期促进肝细胞损伤。在患有糖脂代谢紊乱的肝细胞中可以检测到氧化应激、脂肪变性和异常细胞生长，所有这些都可能导致肝癌的发生。本文重点介绍目前 HCC 中 MDM2-p53 轴的研究，并具体讨论病毒感染和代谢性疾病导致的 MDM2-p53 轴功能障碍对正常肝细胞向肝癌细胞转化的影响。我们还讨论了正在开发的使 HCC 中 MDM2-p53 轴正常化的治疗途径和潜在靶点。