Protein quality control and antigen presentation in the development of hepatitis B-related hepatocellular carcinoma

Chronic hepatitis B virus (HBV) infection remains a leading cause of hepatocellular carcinoma (HCC) worldwide. Although viral integration, chronic inflammation, and immune-mediated injury are established contributors to carcinogenesis, emerging evidence indicates that hepatocellular protein quality control (PQC) pathways and antigen presentation mechanisms play central mechanistic roles in shaping the cellular and immunological environment in which HBV-related HCC develops. HBV imposes an extraordinary folding and degradation burden on hepatocytes through massive production of viral proteins and persistent engagement of the endoplasmic reticulum (ER), cytosolic degradation pathways, and autophagy machinery. Dysregulation of the unfolded protein response (UPR), ER-associated degradation (ERAD), the ubiquitin-proteasome system (UPS), and autophagy enables hepatocytes to tolerate sustained proteotoxic stress while accumulating DNA damage, metabolic alterations, and oncogenic mutations. Simultaneously, HBV disrupts antigen processing and presentation by impairing immunoproteasome function, inhibiting peptide transport and loading, and reducing MHC class I expression. The convergence of PQC dysfunction and antigen presentation impairment is proposed to promote persistent immune evasion, clonal expansion of damaged hepatocytes, thereby increasing the likelihood of malignant transformation. This review integrates recent mechanistic insights into PQC pathways, HBV-host interactions, antigen presentation defects, and their combined contributions to the evolution of HBV-related HCC.