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Regarding HBV treatment, the recent development of nucleoside\/nucleotide analogs (NUC), HBV reverse transcriptase inhibitors, enabled favorable viral control as well as improved prognosis in patients with chronic hepatitis B. However, NUC fails to clear HBV because the formation of covalently closed circular DNA or HBV surface antigen occurs upstream of the point of action of NUC. Recently, we found that acyclic nucleoside phosphonates (ANP) such as adefovir or tenofovir, but not lamivudine or entecavir, induced IFN\u2010\u03bb3 productions in the gastrointestinal tract and modulated lipopolysaccharide (LPS)\u2010mediated cytokine profiles in peripheral blood mononuclear cells, such as interleukin (IL)\u201012p70 induction and IL\u201010 inhibition, which are immunologically favorable cytokine profiles for HBV elimination. Furthermore, IFN\u2010\u03b1, in combination with ANP, showed additional and synergistic effects on IFN\u2010\u03bb3 and IL\u201012p70 production, respectively, while not affecting IL\u201010 levels. Mechanistic analyses of the cytokine modulation by ANP revealed that ANP blocked the mammalian target of the rapamycin (mTOR) pathway by inhibiting Akt translocation to the plasma membrane, thereby inhibiting Akt phosphorylation. As it has been reported that IFN\u2010\u03bb inhibits tumor growth directly or indirectly and the mTOR pathway is generally activated in most cancer cells, ANP might have potential anti\u2010HCC effects. Our <jats:italic>in vitro<\/jats:italic> and <jats:italic>ex vivo<\/jats:italic> findings might stir the debate on whether types of NUC affect the risk of HBV\u2010related HCC incidence.<\/jats:p>","DOI":"10.1111\/jgh.16178","type":"journal-article","created":{"date-parts":[[2023,3,15]],"date-time":"2023-03-15T04:08:37Z","timestamp":1678853317000},"page":"683-691","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Possible biological mechanisms of entecavir <i>versus<\/i> tenofovir disoproxil fumarate on reducing the risk of hepatocellular carcinoma"],"prefix":"10.1111","volume":"38","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3419-6297","authenticated-orcid":false,"given":"Kazumoto","family":"Murata","sequence":"first","affiliation":[{"name":"Division of Virology, Department of Infection and Immunity Jichi Medical University  Shimotsuke Japan"},{"name":"Genome Medical Sciences Project National Center for Global Health and Medicine  Ichikawa Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masashi","family":"Mizokami","sequence":"additional","affiliation":[{"name":"Genome Medical Sciences Project National Center for Global Health and Medicine  Ichikawa Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2023,3,20]]},"reference":[{"key":"e_1_2_5_2_1","unstructured":"WHO.Media Centre Hepatitis B 2014. 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