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Located upstream of the S\u2010open\u2010reading frame of the HBV genome is the pre\u2010S region, which is vital to the viral life cycle. The pre\u2010S region has high variability and many mutations in the pre\u2010S region are associated with several liver diseases, such as fulminant hepatitis (FH), liver cirrhosis (LC), and hepatocellular carcinoma (HCC). In addition, the pre\u2010S region has been applied in the development of several pre\u2010S\u2010based materials and systems to prevent or treat HBV infection. 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