Stem cell–based approaches in hepatitis B virus–related liver disease: therapeutic potential and advances in human-derived research models

Persistent hepatitis B virus (HBV) infection is a major cause of chronic hepatitis, liver fibrosis, cirrhosis, HBV-related acute-on-chronic liver failure (ACLF), and hepatocellular carcinoma. Although nucleos(t)ide analogues and pegylated interferon alfa suppress viral replication and reduce liver-related complications, they have limited capacity to eliminate covalently closed circular DNA (cccDNA) or integrated HBV DNA. Persistent hepatitis B surface antigen (HBsAg) expression, immune dysregulation, fibrogenesis, and impaired hepatic regeneration therefore remain incompletely addressed by current antiviral therapy. Stem cell–based approaches in HBV-related liver disease can be broadly divided into therapeutic and modeling applications. Mesenchymal stromal/stem cells (MSCs) and MSC-derived extracellular vesicles may mitigate injurious inflammation, remodel the hepatic microenvironment, attenuate fibrosis, and support liver regeneration. Current clinical evidence is concentrated mainly in HBV-related ACLF, liver failure, and decompensated cirrhosis, where MSC-based interventions should be viewed as adjunctive disease-modifying strategies alongside standard antiviral therapy and comprehensive supportive care, rather than as direct antiviral or curative treatments. In parallel, embryonic stem cell (ESC)- and induced pluripotent stem cell (iPSC)-derived hepatocytes, liver organoids, and multicellular coculture systems provide physiologically relevant human-derived platforms for modeling persistent HBV infection, HBV/hepatitis D virus coinfection, viral integration-driven hepatocarcinogenesis, and antiviral drug screening. This HBV-specific review integrates therapeutic evidence for stem/stromal cell products with hepatic stem/progenitor biology, mechanisms of viral persistence, and human-derived research models, while preserving the distinction between tissue repair and direct HBV cure. Particular emphasis is placed on the certainty and limitations of clinical evidence, on defining the HBV life-cycle steps supported by human-derived models, and on fit-for-purpose benchmarking. Future progress will require standardized cell products, harmonized clinical endpoints, biomarker-informed patient stratification, long-term safety assessment, and rigorous validation of human-derived models.