{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T21:48:26Z","timestamp":1791236906694,"version":"4.1.0"},"reference-count":82,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2025,12,10]],"date-time":"2025-12-10T00:00:00Z","timestamp":1765324800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"crossref","award":["81870432"],"award-info":[{"award-number":["81870432"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"crossref","award":["81570567"],"award-info":[{"award-number":["81570567"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"crossref","award":["81571994"],"award-info":[{"award-number":["81571994"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100021171","name":"Guangdong Basic and Applied Basic Research Foundation","doi-asserted-by":"crossref","award":["2023A1515010660"],"award-info":[{"award-number":["2023A1515010660"]}],"id":[{"id":"10.13039\/501100021171","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100021171","name":"Guangdong Basic and Applied Basic Research Foundation","doi-asserted-by":"crossref","award":["2024A1515010341"],"award-info":[{"award-number":["2024A1515010341"]}],"id":[{"id":"10.13039\/501100021171","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100021171","name":"Guangdong Basic and Applied Basic Research Foundation","doi-asserted-by":"crossref","award":["2023A1515010449"],"award-info":[{"award-number":["2023A1515010449"]}],"id":[{"id":"10.13039\/501100021171","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100021171","name":"Guangdong Basic and Applied Basic Research Foundation","doi-asserted-by":"crossref","award":["2025A1515010366"],"award-info":[{"award-number":["2025A1515010366"]}],"id":[{"id":"10.13039\/501100021171","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Li Ka Shing Shantou University Foundation","award":["L1111 2008"],"award-info":[{"award-number":["L1111 2008"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Viruses"],"abstract":"<jats:p>(1) Background: Hepatitis B virus (HBV) belongs to the Hepadnaviridae family of viruses that interact with hepatocytes. HBV infection is a major global health problem. Most adults clear the infection quickly after being infected with HBV, while a few people develop chronic HBV infection. It is well-known that the early innate immune response of host cells plays an important role in the fight against virus infection. However, the interactions between HBV and the intrinsic innate immune system of hepatocytes are still not fully understood. The aim of this study was to confirm the interaction between HBV and hepatocytes, and to identify the interferon-stimulated genes (ISGs) regulated by HBx and their expression in association with HBV-associated HCC (HBV-HCC), so that we can refine our understanding of the interaction between HBV and ISGs and its potential influence on HBV-HCC. (2) Methods: We analyzed data concerning the stimulation of IFN-dependent genes in primary human hepatocytes (PHHs) transfected with pathogen DNA mimetics or infected with HBV in the GSE69590 database. Bioinformatic methods, such as GSEA, GO, and KEGG, were used to analyze the differentially expressed innate immunity genes and their related pathways to identify candidate intrinsic innate immune factors. qPCR on HepG2 and Huh7 cells, which highly express HBx, was used to detect relevant intrinsic innate immune factors. qPCR, RNAi, and Elisa methods were used to identify intrinsic innate immune factors in HBV-integrated HepG2.2.15 cells, and bioinformatics analysis was conducted on the HBV-infected tissues and cells in the GEO database. (3) Results: Inhibition of the JAK-STAT pathway enhanced HBV replication in HepG2 cells transfected with HBV plasmid and HepG2-NTCP cells infected with HBV. GSEA analysis of the GSE69590 data revealed significant changes in intrinsic innate immune pathways during HBV infection with PHH for 40 h. A total of 84 differentially expressed, candidate innate immunity genes were identified in GSE69590. Validation showed that TRIM22 and TRIM56 were down-regulated when HBx was expressed. Consistently, TRIM22 and TRIM56 were up-regulated following inhibition of HBx by transfection of HBx siRNA into HepG2.2.15 cells, and HBV pgRNA was up-regulated following down-regulated expression of TRIM22 and TRIM56 in HEK293 cells. Receiver operating characteristics (ROC) and overall survival (OS) analysis of 204 HBV-HCC patients showed that expression of TRIM22 was closely associated with HBV-HCC, and high expression of TRIM22 was associated with longer survival. (4) Conclusions: Innate immunity genes TRIM22 and TRIM56 are regulated by HBx, and higher expression of TRIM22 is closely related to longer survival of HBV-HCC patients.<\/jats:p>","DOI":"10.3390\/v17121599","type":"journal-article","created":{"date-parts":[[2025,12,10]],"date-time":"2025-12-10T14:22:40Z","timestamp":1765376560000},"page":"1599","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["The Intrinsic Innate Immunity of Hepatocytes Suppresses HBV Replication and Is Antagonized by HBx"],"prefix":"10.3390","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4611-134X","authenticated-orcid":false,"given":"Chui","family":"Zeng","sequence":"first","affiliation":[{"name":"Stem Cell Research Center, Shantou University Medical College, Shantou 515041, China"},{"name":"The Center for Reproductive Medicine, Shantou University Medical College, Shantou 515041, China"},{"name":"Guangdong Provincial Key Laboratory of Infectious Diseases and Molecular Immunopathology, Shantou University Medical College, Shantou 515041, China"},{"name":"Guangzhou Women and Children\u2019s Medical Center, Guangzhou Medical University, Guangzhou 510120, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fayed Attia Koutb","family":"Megahed","sequence":"additional","affiliation":[{"name":"Stem Cell Research Center, Shantou University Medical College, Shantou 515041, China"},{"name":"The Center for Reproductive Medicine, Shantou University Medical College, Shantou 515041, China"},{"name":"Guangdong Provincial Key Laboratory of Infectious Diseases and Molecular Immunopathology, Shantou University Medical College, Shantou 515041, China"},{"name":"Department of Nucleic Acid Researches, Genetic Engineering and Biotechnology Research Institute, General Authority-City of Scientific Researches and Technological Applications, Alexandria 21934, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yiqiong","family":"Guo","sequence":"additional","affiliation":[{"name":"Stem Cell Research Center, Shantou University Medical College, Shantou 515041, China"},{"name":"The Center for Reproductive Medicine, Shantou University Medical College, Shantou 515041, China"},{"name":"Guangdong Provincial Key Laboratory of Infectious Diseases and Molecular Immunopathology, Shantou University Medical College, Shantou 515041, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dongmei","family":"Sun","sequence":"additional","affiliation":[{"name":"Pingdi Public Health Service Center, Longgang District, Shenzhen 518117, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yaru","family":"Wang","sequence":"additional","affiliation":[{"name":"Stem Cell Research Center, Shantou University Medical College, Shantou 515041, China"},{"name":"The Center for Reproductive Medicine, Shantou University Medical College, Shantou 515041, China"},{"name":"Guangdong Provincial Key Laboratory of Infectious Diseases and Molecular Immunopathology, Shantou University Medical College, Shantou 515041, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qin","family":"Liu","sequence":"additional","affiliation":[{"name":"Stem Cell Research Center, Shantou University Medical College, Shantou 515041, China"},{"name":"The Center for Reproductive Medicine, Shantou University Medical College, Shantou 515041, China"},{"name":"Guangdong Provincial Key Laboratory of Infectious Diseases and Molecular Immunopathology, Shantou University Medical College, Shantou 515041, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanwei","family":"Bi","sequence":"additional","affiliation":[{"name":"Stem Cell Research Center, Shantou University Medical College, Shantou 515041, China"},{"name":"The Center for Reproductive Medicine, Shantou University Medical College, Shantou 515041, China"},{"name":"Guangdong Provincial Key Laboratory of Infectious Diseases and Molecular Immunopathology, Shantou University Medical College, Shantou 515041, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinghang","family":"Li","sequence":"additional","affiliation":[{"name":"Stem Cell Research Center, Shantou University Medical College, Shantou 515041, China"},{"name":"The Center for Reproductive Medicine, Shantou University Medical College, Shantou 515041, China"},{"name":"Guangdong Provincial Key Laboratory of Infectious Diseases and Molecular Immunopathology, Shantou University Medical College, Shantou 515041, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qi","family":"Zhou","sequence":"additional","affiliation":[{"name":"Stem Cell Research Center, Shantou University Medical College, Shantou 515041, China"},{"name":"The Center for Reproductive Medicine, Shantou University Medical College, Shantou 515041, China"},{"name":"Guangdong Provincial Key Laboratory of Infectious Diseases and Molecular Immunopathology, Shantou University Medical College, Shantou 515041, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qingdong","family":"Xie","sequence":"additional","affiliation":[{"name":"Stem Cell Research Center, Shantou University Medical College, Shantou 515041, China"},{"name":"The Center for Reproductive Medicine, Shantou University Medical College, Shantou 515041, China"},{"name":"Guangdong Provincial Key Laboratory of Infectious Diseases and Molecular Immunopathology, Shantou University Medical College, Shantou 515041, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3325-8062","authenticated-orcid":false,"given":"Pingnan","family":"Sun","sequence":"additional","affiliation":[{"name":"Stem Cell Research Center, Shantou University Medical College, Shantou 515041, China"},{"name":"The Center for Reproductive 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Biomark. Prev."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"e609","DOI":"10.1016\/S2214-109X(16)30143-7","article-title":"Global burden of cancers attributable to infections in 2012: A synthetic analysis","volume":"4","author":"Plummer","year":"2016","journal-title":"Lancet Glob. Health"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"375","DOI":"10.1016\/j.cld.2013.05.002","article-title":"HBV infection and hepatocellular carcinoma","volume":"17","author":"Iavarone","year":"2013","journal-title":"Clin. Liver Dis."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"4683","DOI":"10.3390\/v6114683","article-title":"Hepatitis B virus HBx protein interactions with the ubiquitin proteasome system","volume":"6","author":"Minor","year":"2014","journal-title":"Viruses"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1439","DOI":"10.1099\/vir.0.81920-0","article-title":"The immune response during hepatitis B virus infection","volume":"87","author":"Bertoletti","year":"2006","journal-title":"J. Gen. Virol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1038\/nri1573","article-title":"Immunology of hepatitis B virus and hepatitis C virus infection","volume":"5","author":"Rehermann","year":"2005","journal-title":"Nat. Rev. Immunol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1289","DOI":"10.1053\/j.gastro.2009.06.054","article-title":"Temporal analysis of early immune responses in patients with acute hepatitis B virus infection","volume":"137","author":"Dunn","year":"2009","journal-title":"Gastroenterology"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1779","DOI":"10.1002\/hep.29348","article-title":"Hepatitis B virus evades innate immunity of hepatocytes but activates cytokine production by macrophages","volume":"66","author":"Cheng","year":"2017","journal-title":"Hepatology"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"12193","DOI":"10.1073\/pnas.1412631111","article-title":"Modeling host interactions with hepatitis B virus using primary and induced pluripotent stem cell-derived hepatocellular systems","volume":"111","author":"Shlomai","year":"2014","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"630","DOI":"10.4049\/jimmunol.1502677","article-title":"Hepatitis B Virus and DNA Stimulation Trigger a Rapid Innate Immune Response through NF-kappaB","volume":"197","author":"Yoneda","year":"2016","journal-title":"J. Immunol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1016\/j.immuni.2014.12.016","article-title":"The RNA sensor RIG-I dually functions as an innate sensor and direct antiviral factor for hepatitis B virus","volume":"42","author":"Sato","year":"2015","journal-title":"Immunity"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1148","DOI":"10.1126\/science.1081315","article-title":"Triggering the interferon antiviral response through an IKK-related pathway","volume":"300","author":"Sharma","year":"2003","journal-title":"Science"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"194","DOI":"10.1016\/j.it.2016.12.004","article-title":"Crosstalk between Cytoplasmic RIG-I and STING Sensing Pathways","volume":"38","author":"Zevini","year":"2017","journal-title":"Trends Immunol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"3264","DOI":"10.4049\/jimmunol.1300512","article-title":"Melanoma differentiation-associated gene 5 senses hepatitis B virus and activates innate immune signaling to suppress virus replication","volume":"191","author":"Lu","year":"2013","journal-title":"J. Immunol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"144","DOI":"10.1111\/febs.13563","article-title":"The cyclic GMP-AMP synthetase-STING signaling pathway is required for both the innate immune response against HBV and the suppression of HBV assembly","volume":"283","author":"Dansako","year":"2016","journal-title":"FEBS J."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"377","DOI":"10.1189\/jlb.0812395","article-title":"Interferon-lambda (IFN-lambda) induces signal transduction and gene expression in human hepatocytes, but not in lymphocytes or monocytes","volume":"93","author":"Dickensheets","year":"2013","journal-title":"J. Leukoc. Biol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"204","DOI":"10.1016\/j.stemcr.2014.04.018","article-title":"Modulating innate immunity improves hepatitis C virus infection and replication in stem cell-derived hepatocytes","volume":"3","author":"Zhou","year":"2014","journal-title":"Stem Cell Rep."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Wang, H., and Ryu, W.S. (2010). Hepatitis B virus polymerase blocks pattern recognition receptor signaling via interaction with DDX3: Implications for immune evasion. PLoS Pathog., 6.","DOI":"10.1371\/journal.ppat.1000986"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"2080","DOI":"10.1099\/vir.0.020552-0","article-title":"Hepatitis B virus polymerase inhibits RIG-I- and Toll-like receptor 3-mediated beta interferon induction in human hepatocytes through interference with interferon regulatory factor 3 activation and dampening of the interaction between TBK1\/IKKepsilon and DDX3","volume":"91","author":"Yu","year":"2010","journal-title":"J. Gen. Virol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"470","DOI":"10.1002\/hep.26064","article-title":"Hepatitis B virus polymerase impairs interferon-alpha-induced STA T activation through inhibition of importin-alpha5 and protein kinase C-delta","volume":"57","author":"Chen","year":"2013","journal-title":"Hepatology"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1158","DOI":"10.4049\/jimmunol.0903874","article-title":"The hepatitis B virus X protein disrupts innate immunity by downregulating mitochondrial antiviral signaling protein","volume":"185","author":"Wei","year":"2010","journal-title":"J. Immunol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"987","DOI":"10.1128\/JVI.01825-10","article-title":"Hepatitis B virus regulatory HBx protein binds to adaptor protein IPS-1 and inhibits the activation of beta interferon","volume":"85","author":"Kumar","year":"2011","journal-title":"J. Virol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"166","DOI":"10.1136\/gutjnl-2016-312742","article-title":"Suppression of interferon-mediated anti-HBV response by single CpG methylation in the 5\u2019-UTR of TRIM22","volume":"67","author":"Lim","year":"2018","journal-title":"Gut"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"719","DOI":"10.1016\/j.bbrc.2015.05.130","article-title":"Innate immune evasion by hepatitis B virus-mediated downregulation of TRIF","volume":"463","author":"Hong","year":"2015","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"2073","DOI":"10.1099\/vir.0.18966-0","article-title":"Hepatitis B virus downregulates the human interferon-inducible MxA promoter through direct interaction of precore\/core proteins","volume":"84","author":"Fernandez","year":"2003","journal-title":"J. Gen. Virol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1132","DOI":"10.1002\/hep.22751","article-title":"Hepatitis B virus suppresses toll-like receptor-mediated innate immune responses in murine parenchymal and nonparenchymal liver cells","volume":"49","author":"Wu","year":"2009","journal-title":"Hepatology"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"102","DOI":"10.1002\/hep.21482","article-title":"Regulation of Toll-like receptor-2 expression in chronic hepatitis B by the precore protein","volume":"45","author":"Visvanathan","year":"2007","journal-title":"Hepatology"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"762","DOI":"10.1016\/j.jhep.2010.12.042","article-title":"The hepatitis B e antigen (HBeAg) targets and suppresses activation of the toll-like receptor signaling pathway","volume":"55","author":"Lang","year":"2011","journal-title":"J. Hepatol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"644","DOI":"10.1016\/0042-6822(91)90535-J","article-title":"Temporal aspects of major viral transcript expression in Hep G2 cells transfected with cloned hepatitis B virus DNA: With emphasis on the X transcript","volume":"185","author":"Wu","year":"1991","journal-title":"Virology"},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Niu, C., Livingston, C.M., Li, L., Beran, R.K., Daffis, S., Ramakrishnan, D., Burdette, D., Peiser, L., Salas, E., and Ramos, H. (2017). The Smc5\/6 Complex Restricts HBV when Localized to ND10 without Inducing an Innate Immune Response and Is Counteracted by the HBV X Protein Shortly after Infection. PloS ONE, 12.","DOI":"10.1371\/journal.pone.0169648"},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Kornyeyev, D., Ramakrishnan, D., Voitenleitner, C., Livingston, C.M., Xing, W., Hung, M., Kwon, H.J., Fletcher, S.P., and Beran, R.K. (2019). Spatiotemporal Analysis of Hepatitis B Virus X Protein in Primary Human Hepatocytes. J. Virol., 93.","DOI":"10.1128\/JVI.00248-19"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"733","DOI":"10.1016\/j.febslet.2014.01.017","article-title":"Hepatitis B virus X increases immune cell recruitment by induction of chemokine SDF-1","volume":"588","author":"Cho","year":"2014","journal-title":"FEBS Lett."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1093\/humrep\/dead235","article-title":"The influence of male HBV infection on sperm quality, embryonic development, and assisted reproductive outcomes","volume":"39","author":"Meng","year":"2024","journal-title":"Hum. Reprod."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"207","DOI":"10.1093\/nar\/30.1.207","article-title":"Gene Expression Omnibus: NCBI gene expression and hybridization array data repository","volume":"30","author":"Edgar","year":"2002","journal-title":"Nucleic Acids Res."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"D991","DOI":"10.1093\/nar\/gks1193","article-title":"NCBI GEO: Archive for functional genomics data sets--update","volume":"41","author":"Barrett","year":"2013","journal-title":"Nucleic Acids Res."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"D1228","DOI":"10.1093\/nar\/gks1147","article-title":"InnateDB: Systems biology of innate immunity and beyond--recent updates and continuing curation","volume":"41","author":"Breuer","year":"2013","journal-title":"Nucleic Acids Res."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"W199","DOI":"10.1093\/nar\/gkz401","article-title":"WebGestalt 2019: Gene set analysis toolkit with revamped UIs and APIs","volume":"47","author":"Liao","year":"2019","journal-title":"Nucleic Acids Res."},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Bardou, P., Mariette, J., Escudie, F., Djemiel, C., and Klopp, C. (2014). jvenn: An interactive Venn diagram viewer. BMC Bioinform., 15.","DOI":"10.1186\/1471-2105-15-293"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"284","DOI":"10.1089\/omi.2011.0118","article-title":"clusterProfiler: An R package for comparing biological themes among gene clusters","volume":"16","author":"Yu","year":"2012","journal-title":"OMICS"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1830","DOI":"10.1093\/bioinformatics\/btt285","article-title":"Pathview: An R\/Bioconductor package for pathway-based data integration and visualization","volume":"29","author":"Luo","year":"2013","journal-title":"Bioinformatics"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"7252","DOI":"10.1158\/1078-0432.CCR-04-0713","article-title":"X-tile: A new bio-informatics tool for biomarker assessment and outcome-based cut-point optimization","volume":"10","author":"Camp","year":"2004","journal-title":"Clin. Cancer Res."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1038\/cdd.2008.144","article-title":"Hepatitis B virus core protein inhibits TRAIL-induced apoptosis of hepatocytes by blocking DR5 expression","volume":"16","author":"Du","year":"2009","journal-title":"Cell Death Differ."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"2507","DOI":"10.1111\/jcmm.14944","article-title":"Defined host factors support HBV infection in non-hepatic 293T cells","volume":"24","author":"Yang","year":"2020","journal-title":"J. Cell Mol. Med."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"799","DOI":"10.1038\/nrmicro1248","article-title":"TRIM family proteins: Retroviral restriction and antiviral defence","volume":"3","author":"Nisole","year":"2005","journal-title":"Nat. Rev. Microbiol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1147","DOI":"10.1002\/bies.20304","article-title":"TRIM\/RBCC, a novel class of \u2018single protein RING finger\u2019 E3 ubiquitin ligases","volume":"27","author":"Meroni","year":"2005","journal-title":"Bioessays"},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Uchil, P.D., Quinlan, B.D., Chan, W.T., Luna, J.M., and Mothes, W. (2008). TRIM E3 ligases interfere with early and late stages of the retroviral life cycle. PLoS Pathog., 4.","DOI":"10.1371\/journal.ppat.0040016"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"3733","DOI":"10.1128\/JVI.02546-10","article-title":"TRIM56 is a virus- and interferon-inducible E3 ubiquitin ligase that restricts pestivirus infection","volume":"85","author":"Wang","year":"2011","journal-title":"J. Virol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"502","DOI":"10.1016\/j.bbrc.2008.07.070","article-title":"Identification of TRIM22 as a RING finger E3 ubiquitin ligase","volume":"374","author":"Duan","year":"2008","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"765","DOI":"10.1016\/j.immuni.2010.10.013","article-title":"The ubiquitin ligase TRIM56 regulates innate immune responses to intracellular double-stranded DNA","volume":"33","author":"Tsuchida","year":"2010","journal-title":"Immunity"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"613","DOI":"10.1038\/s41467-018-02936-3","article-title":"TRIM56-mediated monoubiquitination of cGAS for cytosolic DNA sensing","volume":"9","author":"Seo","year":"2018","journal-title":"Nat. Commun."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"36404","DOI":"10.1074\/jbc.M112.397075","article-title":"TRIM56 is an essential component of the TLR3 antiviral signaling pathway","volume":"287","author":"Shen","year":"2012","journal-title":"J. Biol. Chem."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"10202","DOI":"10.1158\/0008-5472.CAN-10-2607","article-title":"A unique metastasis gene signature enables prediction of tumor relapse in early-stage hepatocellular carcinoma patients","volume":"70","author":"Roessler","year":"2010","journal-title":"Cancer Res."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"136","DOI":"10.1186\/s12943-017-0680-1","article-title":"STAT3-mediated upregulation of lncRNA HOXD-AS1 as a ceRNA facilitates liver cancer metastasis by regulating SOX4","volume":"16","author":"Wang","year":"2017","journal-title":"Mol. Cancer"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"6275","DOI":"10.1158\/1078-0432.CCR-06-2236","article-title":"Identification and validation of a novel gene signature associated with the recurrence of human hepatocellular carcinoma","volume":"13","author":"Wang","year":"2007","journal-title":"Clin. Cancer Res."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"230","DOI":"10.1186\/s12967-014-0230-1","article-title":"Viral expression and molecular profiling in liver tissue versus microdissected hepatocytes in hepatitis B virus-associated hepatocellular carcinoma","volume":"12","author":"Melis","year":"2014","journal-title":"J. Transl. Med."},{"key":"ref_56","doi-asserted-by":"crossref","unstructured":"Meng, Z., Chen, Y., and Lu, M. (2019). Advances in Targeting the Innate and Adaptive Immune Systems to Cure Chronic Hepatitis B Virus Infection. Front. Immunol., 10.","DOI":"10.3389\/fimmu.2019.03127"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1056\/NEJMra2211764","article-title":"New Approaches to Chronic Hepatitis B. N","volume":"388","author":"Dusheiko","year":"2023","journal-title":"Engl. J. Med."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"907","DOI":"10.1111\/j.1462-5822.2006.00716.x","article-title":"Interferon signalling network in innate defence","volume":"8","author":"Takaoka","year":"2006","journal-title":"Cell Microbiol."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"1659","DOI":"10.1136\/gutjnl-2019-319354","article-title":"Efficient acute and chronic infection of stem cell-derived hepatocytes by hepatitis C virus","volume":"69","author":"Carpentier","year":"2020","journal-title":"Gut"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"1778","DOI":"10.1053\/j.gastro.2018.01.034","article-title":"Hepatitis B Virus Does Not Interfere With Innate Immune Responses in the Human Liver","volume":"154","author":"Suslov","year":"2018","journal-title":"Gastroenterology"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"1791","DOI":"10.1053\/j.gastro.2018.01.044","article-title":"HBV Bypasses the Innate Immune Response and Does Not Protect HCV from Antiviral Activity of Interferon","volume":"154","author":"Mutz","year":"2018","journal-title":"Gastroenterology"},{"key":"ref_62","doi-asserted-by":"crossref","unstructured":"Lauterbach-Riviere, L., Bergez, M., Monch, S., Qu, B., Riess, M., Vondran, F.W.R., Liese, J., Hornung, V., Urban, S., and Konig, R. (2020). Hepatitis B Virus DNA is a Substrate for the cGAS\/STING Pathway but is not Sensed in Infected Hepatocytes. Viruses, 12.","DOI":"10.3390\/v12060592"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"98","DOI":"10.1038\/s41467-020-20316-8","article-title":"Hepatitis B virus rigs the cellular metabolome to avoid innate immune recognition","volume":"12","author":"Zhou","year":"2021","journal-title":"Nat. Commun."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1093\/jmcb\/mjz104","article-title":"An HBV-encoded miRNA activates innate immunity to restrict HBV replication","volume":"12","author":"Zhao","year":"2020","journal-title":"J. Mol. Cell Biol."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"1314","DOI":"10.1016\/j.jhep.2015.07.014","article-title":"Early inhibition of hepatocyte innate responses by hepatitis B virus","volume":"63","author":"Luangsay","year":"2015","journal-title":"J. Hepatol."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"534","DOI":"10.1158\/0008-5472.CAN-18-2357","article-title":"A GYS2\/p53 Negative Feedback Loop Restricts Tumor Growth in HBV-Related Hepatocellular Carcinoma","volume":"79","author":"Chen","year":"2019","journal-title":"Cancer Res."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"3260","DOI":"10.3934\/mbe.2020186","article-title":"Multi-scale modeling identifies the role of p53-Gys2 negative feedback loop in cellular homeostasis","volume":"17","author":"Sun","year":"2020","journal-title":"Math. Biosci. Eng."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"e0128723","DOI":"10.1128\/jvi.01287-23","article-title":"Oxidative stress sensor Keap1 recognizes HBx protein to activate the Nrf2\/ARE signaling pathway, thereby inhibiting hepatitis B virus replication","volume":"97","author":"Ariffianto","year":"2023","journal-title":"J. Virol."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"104533","DOI":"10.4254\/wjh.v17.i6.104533","article-title":"Hepatocyte-intrinsic innate immunity in hepatitis B virus infection: A focused review","volume":"17","author":"Chen","year":"2025","journal-title":"World J. Hepatol."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1007\/s00281-012-0331-y","article-title":"The role of innate immunity in HBV infection","volume":"35","author":"Han","year":"2013","journal-title":"Semin. Immunopathol."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"1871","DOI":"10.1038\/s41423-021-00729-1","article-title":"Hepatitis B virus evades immune recognition via RNA adenosine deaminase ADAR1-mediated viral RNA editing in hepatocytes","volume":"18","author":"Wang","year":"2021","journal-title":"Cell Mol. Immunol."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"792","DOI":"10.1038\/nrc3139","article-title":"TRIM proteins and cancer","volume":"11","author":"Hatakeyama","year":"2011","journal-title":"Nat. Rev. Cancer"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"6669","DOI":"10.1073\/pnas.0401771101","article-title":"Genomic analysis of the host response to hepatitis B virus infection","volume":"101","author":"Wieland","year":"2004","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_74","doi-asserted-by":"crossref","unstructured":"Lee, Y.S., Ko, E., Yoon, E.L., Jung, Y.K., Kim, J.H., Seo, Y.S., Yim, H.J., Kim, K.H., Kwon, S.Y., and Yeon, J.E. (2020). Multiplexed Proteomic Approach for Identification of Serum Biomarkers in Hepatocellular Carcinoma Patients with Normal AFP. J. Clin. Med., 9.","DOI":"10.3390\/jcm9020323"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"424","DOI":"10.1002\/hep.23011","article-title":"Tripartite motif-containing 22 inhibits the activity of hepatitis B virus core promoter, which is dependent on nuclear-located RING domain","volume":"50","author":"Gao","year":"2009","journal-title":"Hepatology"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"392","DOI":"10.1016\/j.chom.2016.08.005","article-title":"Identification of Interferon-Stimulated Genes with Antiretroviral Activity","volume":"20","author":"Kane","year":"2016","journal-title":"Cell Host Microbe"},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"2287","DOI":"10.1128\/JVI.02760-14","article-title":"Hepatitis B virus polymerase disrupts K63-linked ubiquitination of STING to block innate cytosolic DNA-sensing pathways","volume":"89","author":"Liu","year":"2015","journal-title":"J. Virol."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"105406","DOI":"10.1016\/j.antiviral.2022.105406","article-title":"TRIM56 impairs HBV infection and replication by inhibiting HBV core promoter activity","volume":"207","author":"Tian","year":"2022","journal-title":"Antivir. Res."},{"key":"ref_79","doi-asserted-by":"crossref","unstructured":"Zhang, S., Guo, J.T., Wu, J.Z., and Yang, G. (2013). Identification and characterization of multiple TRIM proteins that inhibit hepatitis B virus transcription. PloS One, 8.","DOI":"10.1371\/journal.pone.0070001"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"467","DOI":"10.1038\/s41420-023-01755-w","article-title":"A small molecule iCDM-34 identified by in silico screening suppresses HBV DNA through activation of aryl hydrocarbon receptor","volume":"9","author":"Furutani","year":"2023","journal-title":"Cell Death Discov."},{"key":"ref_81","doi-asserted-by":"crossref","unstructured":"Furutani, Y., Toguchi, M., Shiozaki-Sato, Y., Qin, X.Y., Ebisui, E., Higuchi, S., Sudoh, M., Suzuki, H., Takahashi, N., and Watashi, K. (2019). An interferon-like small chemical compound CDM-3008 suppresses hepatitis B virus through induction of interferon-stimulated genes. PloS One, 14.","DOI":"10.1371\/journal.pone.0216139"},{"key":"ref_82","doi-asserted-by":"crossref","unstructured":"Megahed, F.A.K., Zhou, X., and Sun, P. (2020). The Interactions between HBV and the Innate Immunity of Hepatocytes. Viruses, 12.","DOI":"10.3390\/v12030285"}],"container-title":["Viruses"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4915\/17\/12\/1599\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,12,12]],"date-time":"2025-12-12T05:14:51Z","timestamp":1765516491000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4915\/17\/12\/1599"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,12,10]]},"references-count":82,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2025,12]]}},"alternative-id":["v17121599"],"URL":"https:\/\/doi.org\/10.3390\/v17121599","relation":{},"ISSN":["1999-4915"],"issn-type":[{"value":"1999-4915","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,12,10]]}}}