fig1

Figure 1. Schematic representation of the impact of HBV infection on HCC development. (1) Hepatic steatosis with high-fat diet can reduce HBV replication, increase HBsAg secretion, and inhibit liver inflammation, and probably reduce the risk of HCC; (2) Some types of HBV preS/S variants can induce an imbalanced HBV production and secretion, leading to ER stress-dependent and/or independent signals to promote HCC development (Reviewed by Pollicino et al.^[40]); (3) PreS mutations related to OBI post HepB vaccination occur. The OBI-related variants display the alteration of amino acid properties in large-S protein and result in HBsAg retention in hepatocyte ER. PreS variant-infected hepatocytes elevate the generation of abnormal ceramides after overload of free fatty acids. The abnormal ceramides, together with HBV proteins, co-activate NLRP3 inflammasome to increase the production of inflammatory cytokines from liver macrophages, increasing the risk of HCC. HBV: Hepatitis B virus; HCC: hepatocellular carcinoma; HBsAg: hepatitis B surface antigen; ER: endoplasmic reticulum; OBI: occult hepatitis B infection; NLRP3: NOD-like receptor protein 3.