The Malignant Transformation of Viral Hepatitis to Hepatocellular Carcinoma: Mechanisms and Interventions

ABSTRACT Hepatocellular carcinoma (HCC) is a leading cause of cancer‐related mortality globally, predominantly associated with chronic hepatitis B virus (HBV) and hepatitis C virus (HCV) infections. These infections drive persistent liver inflammation, culminating in cellular dysregulation, fibrosis, and cancer. Despite advancements in targeted therapies, drug resistance and the lack of reliable biomarkers for patient stratification still terribly hinder the treatment of viral HCC. To this end, the review delves into the intricate mechanisms underlying the malignant transformation of viral hepatitis to HCC, including viral integration, genomic instability, epigenetic modifications, oxidative stress, gut microbiota dysbiosis, chronic inflammation, immune escape, and abnormal signaling pathways, highlighting their complex interactions and synergies. Cutting‐edge preclinical and clinical advancements in HCC management, including lifestyle modifications, drug therapies, immunotherapies, gene‐based approaches, and innovative treatments, are further investigated, with particular priority given to their therapeutic potential and future applications in overcoming current limitations. By synthesizing recent scientific and clinical insights, this review aims to deepen the understanding of HCC pathogenesis in the context of chronic viral hepatitis, paving the way for novel therapeutic targets and personalized treatment strategies, ultimately improving patient outcomes.