Double-Edged Sword: HBV-Driven Lipid Metabolism Remodeling in Hepatocarcinogenesis Through Ferroptosis Regulation

Chronic hepatitis B virus (HBV) infection remains a leading cause of hepatocellular carcinoma (HCC) worldwide, particularly in Asia. Although nucleos(t)ide analogs suppress viral replication and reduce HCC incidence, residual risk persists, highlighting the need to better understand HBV-driven hepatocarcinogenesis. HBV alters host transcription, DNA repair, lipid metabolism, and the hepatic immune microenvironment. These changes help sustain liver injury, fibrogenesis, and malignant transformation. Ferroptosis, an iron-dependent form of programmed cell death driven by excessive lipid peroxidation, has emerged as an important mechanism in this context, because the liver is central to iron and lipid metabolism. Here, we propose that HBV-driven lipid remodeling shapes ferroptosis susceptibility in a stage-dependent, double-edged manner. During chronic infection, oxidative stress and enrichment of peroxidation-prone lipid substrates may promote ferroptosis-associated hepatocyte injury, immune dysregulation, and fibrosis. After malignant transformation, HBV-related oncogenic programs may instead favor ferroptosis evasion through altered lipid composition and strengthened antioxidant defenses, thereby supporting tumor survival and progression. In this review, we summarize mechanisms linking HBV, lipid metabolic remodeling, and ferroptosis while distinguishing direct HBV-related evidence from findings inferred from other liver disease or cancer models. This HBV-ferroptosis framework may help refine risk stratification and suggest new therapeutic opportunities in HBV-related HCC.