Bridging viral hepatitis and liver cancer: Emerging concepts in pathogenesis and therapeutic innovation

Abstract

Background: Viral hepatitis, particularly hepatitis B virus (HBV) and hepatitis C virus (HCV) infections, represent the predominant etiological factors for hepatocellular carcinoma (HCC) worldwide. HBV and HCV drive hepatocellular malignant transformation through complex molecular mechanisms that are both distinct and overlapping. Comprehensive elucidation of these mechanisms, particularly the role of viral-mediated remodeling of the tumor microenvironment, is crucial for developing novel preventive and diagnostic strategies as well as personalized therapeutic approaches.

Aim: This review aims to systematically elucidate the key molecular mechanisms underlying HBV- and HCV-related HCC development and progression (including virus-specific pathways and common pathways), to explore the translational potential of these mechanisms in clinical medicine, and to provide perspectives on future research frontiers.

Results: This review systematically elucidates the pathogenic mechanisms of HBV- and HCV-related HCC and provides comprehensive analysis of the common molecular mechanisms underlying viral hepatitis-to-HCC transformation. For HBV-related HCC, we focus on analyzing the following oncogenic mechanisms: genomic instability caused by HBV DNA integration, oncogenic effects of HBV proteins, and the impact of virus infection-mediated tumor microenvironment remodeling on immune responses. For HCV-related HCC, we focus on exploring the following oncogenic mechanisms: oncogenic mechanisms of viral proteins, virus infection-mediated metabolic disorders, functional dysregulation of immune cells in the microenvironment, and virus-induced hepatic fibrosis. Furthermore, we thoroughly investigated the common mechanisms underlying viral hepatitis-to-HCC transformation, including the construction of pro-inflammatory factor networks in chronic inflammatory microenvironments, virus-induced epigenetic alterations, and genomic instability. Based on current research, we further discuss future research directions and perspectives in this field.

Conclusion: This review systematically elucidates the pathogenic mechanisms of HBV- and HCV-related HCC and provides comprehensive analysis of the common molecular mechanisms underlying viral hepatitis-to-HCC transformation, with particular emphasis on the remodeling effects of viral infection on the HCC microenvironment, which hold significant clinical implications for developing novel preventive strategies, diagnostic biomarkers, and personalized therapeutic approaches. Through systematic analysis of the long-term effects of virus infection-induced epigenetic reprogramming in HCC development and progression, combined with multi-omics data to construct HCC risk prediction models, our findings provide scientific evidence for the development of early screening and precision treatment strategies. Meanwhile, investigating the relationship between viral integration patterns and HCC prognosis, and developing novel molecular classification methods, will facilitate the design of more individualized and precise treatment regimens for patients. Additionally, utilizing cutting-edge artificial intelligence technologies and developing innovative research approaches such as viral hepatitis-related liver organoid models will also provide novel insights and methodologies for reducing the incidence and mortality of viral hepatitis-related HCC.

Keywords

Chronic viral hepatitis / Hepatitis B / Hepatitis C / Hepatocellular carcinoma

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