{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T01:49:36Z","timestamp":1790732976840,"version":"4.1.0"},"reference-count":133,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,4,10]],"date-time":"2026-04-10T00:00:00Z","timestamp":1775779200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:p>Chronic hepatitis B virus (HBV) infection remains a leading cause of hepatocellular carcinoma (HCC) worldwide. Although viral integration, chronic inflammation, and immune-mediated injury are established contributors to carcinogenesis, emerging evidence indicates that hepatocellular protein quality control (PQC) pathways and antigen presentation mechanisms play central mechanistic roles in shaping the cellular and immunological environment in which HBV-related HCC develops. HBV imposes an extraordinary folding and degradation burden on hepatocytes through massive production of viral proteins and persistent engagement of the endoplasmic reticulum (ER), cytosolic degradation pathways, and autophagy machinery. Dysregulation of the unfolded protein response (UPR), ER-associated degradation (ERAD), the ubiquitin-proteasome system (UPS), and autophagy enables hepatocytes to tolerate sustained proteotoxic stress while accumulating DNA damage, metabolic alterations, and oncogenic mutations. Simultaneously, HBV disrupts antigen processing and presentation by impairing immunoproteasome function, inhibiting peptide transport and loading, and reducing MHC class I expression. The convergence of PQC dysfunction and antigen presentation impairment is proposed to promote persistent immune evasion, clonal expansion of damaged hepatocytes, thereby increasing the likelihood of malignant transformation. This review integrates recent mechanistic insights into PQC pathways, HBV-host interactions, antigen presentation defects, and their combined contributions to the evolution of HBV-related HCC.<\/jats:p>","DOI":"10.3389\/fphar.2026.1786614","type":"journal-article","created":{"date-parts":[[2026,4,10]],"date-time":"2026-04-10T06:05:59Z","timestamp":1775801159000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Protein quality control and antigen presentation in the development of hepatitis B-related hepatocellular carcinoma"],"prefix":"10.3389","volume":"17","author":[{"given":"Lina","family":"An","sequence":"first","affiliation":[{"name":"Department of Integrated Traditional Chinese and Western Medicine, Qingdao Public Health Clinical Center (Qingdao Sixth People\u2019s Hospital)","place":["Qingdao, Shandong, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yidi","family":"Han","sequence":"additional","affiliation":[{"name":"Department of Interventional Medicine, Qingdao Public Health Clinical Center (Qingdao Sixth People\u2019s Hospital)","place":["Qingdao, Shandong, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaohui","family":"Sun","sequence":"additional","affiliation":[{"name":"Department of Research and Education, Qingdao Public Health Clinical Center (Qingdao Sixth People\u2019s Hospital)","place":["Qingdao, Shandong, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lili","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Liver Oncology, Qingdao Public Health Clinical Center (Qingdao Sixth People\u2019s Hospital)","place":["Qingdao, Shandong, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lei","family":"Guo","sequence":"additional","affiliation":[{"name":"Department of Integrated Traditional Chinese and Western Medicine, Qingdao Public Health Clinical Center (Qingdao Sixth People\u2019s Hospital)","place":["Qingdao, Shandong, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,4,10]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"322","DOI":"10.1089\/vim.2019.0042","article-title":"Harmonized autophagy Versus full-fledged hepatitis B virus: victorious or defeated","volume":"32","author":"Abdoli","year":"2019","journal-title":"Viral Immunol."},{"key":"B2","doi-asserted-by":"publisher","first-page":"372","DOI":"10.1136\/gutjnl-2020-322571","article-title":"Therapeutic shutdown of HBV transcripts promotes reappearance of the SMC5\/6 complex and silencing of the viral genome in vivo","volume":"71","author":"Allweiss","year":"2022","journal-title":"Gut"},{"key":"B3","doi-asserted-by":"publisher","first-page":"1400","DOI":"10.1016\/j.ajpath.2023.06.002","article-title":"Oxidative stress\u2013induced liver damage and remodeling of the liver vasculature","volume":"193","author":"Banerjee","year":"2023","journal-title":"Am. J. Pathology"},{"key":"B4","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1038\/s12276-019-0309-0","article-title":"Deacetylation of XBP1s by sirtuin 6 confers resistance to ER stress-induced hepatic steatosis","volume":"51","author":"Bang","year":"2019","journal-title":"Exp. Mol. Med."},{"key":"B5","doi-asserted-by":"publisher","first-page":"200","DOI":"10.1038\/s41590-024-02063-w","article-title":"IRE1\u03b1\u2013XBP1 safeguards hematopoietic stem and progenitor cells by restricting pro-leukemogenic gene programs","volume":"26","author":"Barton","year":"2025","journal-title":"Nat. Immunol."},{"key":"B6","doi-asserted-by":"publisher","first-page":"819","DOI":"10.1016\/j.idc.2011.07.008","article-title":"Interferons as therapeutic agents for infectious diseases","volume":"25","author":"Bergman","year":"2011","journal-title":"Infect. Dis. Clin. North Am."},{"key":"B7","doi-asserted-by":"publisher","first-page":"e423","DOI":"10.1371\/journal.pbio.0040423","article-title":"Autophagy counterbalances endoplasmic reticulum expansion during the unfolded protein response","volume":"4","author":"Bernales","year":"2006","journal-title":"PLOS Biol."},{"key":"B8","doi-asserted-by":"publisher","first-page":"258","DOI":"10.1038\/cmi.2014.79","article-title":"The immune tolerant phase of chronic HBV infection: new perspectives on an old concept","volume":"12","author":"Bertoletti","year":"2015","journal-title":"Cell Mol. Immunol."},{"key":"B9","doi-asserted-by":"publisher","first-page":"145","DOI":"10.3748\/wjg.v22.i1.145","article-title":"Overview of hepatitis B virus mutations and their implications in the management of infection","volume":"22","author":"Caligiuri","year":"2016","journal-title":"World J. Gastroenterol."},{"key":"B10","doi-asserted-by":"publisher","first-page":"396","DOI":"10.1089\/ars.2014.5851","article-title":"Endoplasmic reticulum stress and oxidative stress in cell fate decision and human disease","volume":"21","author":"Cao","year":"2014","journal-title":"Antioxid. Redox Signal"},{"key":"B11","doi-asserted-by":"publisher","first-page":"2357","DOI":"10.1093\/emboj\/20.10.2357","article-title":"26S proteasomes and immunoproteasomes produce mainly N-extended versions of an antigenic peptide","volume":"20","author":"Cascio","year":"2001","journal-title":"EMBO J."},{"key":"B12","doi-asserted-by":"publisher","first-page":"7812","DOI":"10.1128\/JVI.00561-08","article-title":"Properties of subviral particles of hepatitis B virus","volume":"82","author":"Chai","year":"2008","journal-title":"J. Virol."},{"key":"B13","doi-asserted-by":"publisher","first-page":"1621243","DOI":"10.3389\/fimmu.2025.1621243","article-title":"Immunotherapy targeting liver cancer tumor-initiating cells: challenges, mechanisms, and emerging therapeutic horizons","volume":"16","author":"Chai","year":"2025","journal-title":"Front. Immunol."},{"key":"B14","first-page":"373","article-title":"Hepatitis B virus down-regulates expressions of MHC class I molecules on hepatoplastoma cell line","volume":"3","author":"Chen","year":"2006","journal-title":"Cell Mol. Immunol."},{"key":"B15","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1186\/s13046-020-01803-8","article-title":"Hepatitis B virus P protein initiates glycolytic bypass in HBV-related hepatocellular carcinoma via a FOXO3\/miRNA-30b-5p\/MINPP1 axis","volume":"40","author":"Chen","year":"2021","journal-title":"J. Exp. and Clin. Cancer Res."},{"key":"B16","doi-asserted-by":"publisher","first-page":"431","DOI":"10.1042\/BJ20102071","article-title":"Endoplasmic reticulum stress induced by hepatitis B virus X protein enhances cyclo-oxygenase 2 expression via activating transcription factor 4","volume":"435","author":"Cho","year":"2011","journal-title":"Biochem. J."},{"key":"B17","doi-asserted-by":"publisher","first-page":"581","DOI":"10.3892\/ijmm.2012.879","article-title":"Hepatitis B virus X protein inhibits extracellular IFN-\u03b1-mediated signal transduction by downregulation of type I IFN receptor","volume":"29","author":"Cho","year":"2012","journal-title":"Int. J. Mol. Med."},{"key":"B18","doi-asserted-by":"publisher","first-page":"120","DOI":"10.1038\/s41467-022-35584-9","article-title":"Tumor-intrinsic IRE1\u03b1 signaling controls protective immunity in lung cancer","volume":"14","author":"Crowley","year":"2023","journal-title":"Nat. Commun."},{"key":"B19","doi-asserted-by":"publisher","first-page":"173","DOI":"10.1007\/s00281-020-00780-6","article-title":"Epigenetic modulation in chronic hepatitis B virus infection","volume":"42","author":"Dandri","year":"2020","journal-title":"Semin. Immunopathol."},{"key":"B20","doi-asserted-by":"publisher","first-page":"550","DOI":"10.1002\/hep.31725","article-title":"Human hepatitis B virus negatively impacts the protective immune crosstalk between natural killer and dendritic cells","volume":"74","author":"De Pasquale","year":"2021","journal-title":"Hepatology"},{"key":"B21","doi-asserted-by":"publisher","first-page":"386","DOI":"10.1038\/nature17170","article-title":"Hepatitis B virus X protein identifies the Smc5\/6 complex as a host restriction factor","volume":"531","author":"Decorsi\u00e8re","year":"2016","journal-title":"Nature"},{"key":"B22","doi-asserted-by":"publisher","first-page":"e1003937","DOI":"10.1371\/journal.pgen.1003937","article-title":"The stress-regulated transcription factor CHOP promotes hepatic inflammatory gene expression, fibrosis, and oncogenesis","volume":"9","author":"DeZwaan-McCabe","year":"2013","journal-title":"PLoS Genet."},{"key":"B23","doi-asserted-by":"publisher","first-page":"636568","DOI":"10.3389\/fimmu.2021.636568","article-title":"Cancer immune evasion through loss of MHC class I antigen presentation","volume":"12","author":"Dhatchinamoorthy","year":"2021","journal-title":"Front. Immunol."},{"key":"B24","doi-asserted-by":"publisher","first-page":"87","DOI":"10.1016\/s1074-7613(02)00263-7","article-title":"Disulfide bond isomerization and the assembly of MHC class I-peptide complexes","volume":"16","author":"Dick","year":"2002","journal-title":"Immunity"},{"key":"B25","doi-asserted-by":"publisher","first-page":"14507","DOI":"10.1038\/s41598-022-18807-3","article-title":"Airway epithelial immunoproteasome subunit LMP7 protects against rhinovirus infection","volume":"12","author":"Dimasuay","year":"2022","journal-title":"Sci. Rep."},{"key":"B26","doi-asserted-by":"publisher","first-page":"2543","DOI":"10.1007\/s00018-012-0938-0","article-title":"Emerging roles of immunoproteasomes beyond MHC class I antigen processing","volume":"69","author":"Ebstein","year":"2012","journal-title":"Cell Mol. Life Sci."},{"key":"B27","doi-asserted-by":"publisher","first-page":"1264","DOI":"10.1053\/j.gastro.2011.12.061","article-title":"Epidemiology of viral hepatitis and hepatocellular carcinoma","volume":"142","author":"El-Serag Hb","year":"2012","journal-title":"Gastroenterology"},{"key":"B28","doi-asserted-by":"publisher","first-page":"75","DOI":"10.1016\/B978-0-12-397863-9.00003-1","article-title":"Immunoproteasomes: structure, function, and antigen presentation","volume":"109","author":"Ferrington","year":"2012","journal-title":"Prog. Mol. Biol. Transl. Sci."},{"key":"B29","doi-asserted-by":"publisher","first-page":"1674163","DOI":"10.3389\/fimmu.2025.1674163","article-title":"Endoplasmic reticulum stress orchestrates tumor metabolism and immunity: new insights into immunometabolic therapeutics","volume":"16","author":"Fu","year":"2025","journal-title":"Front. Immunol."},{"key":"B30","doi-asserted-by":"publisher","first-page":"97","DOI":"10.1084\/jem.187.1.97","article-title":"Immunoproteasome assembly: cooperative incorporation of interferon \u03b3 (IFN-\u03b3)\u2013inducible subunits","volume":"187","author":"Griffin","year":"1998","journal-title":"J. Exp. Med."},{"key":"B31","doi-asserted-by":"publisher","first-page":"39294","DOI":"10.1074\/jbc.M608085200","article-title":"Lipid-induced extension of apolipoprotein E helix 4 correlates with low density lipoprotein receptor binding ability","volume":"281","author":"Gupta","year":"2006","journal-title":"J. Biol. Chem."},{"key":"B32","doi-asserted-by":"publisher","first-page":"e202111068","DOI":"10.1083\/jcb.202111068","article-title":"Antigen-derived peptides engage the ER stress sensor IRE1\u03b1 to curb dendritic cell cross-presentation","volume":"221","author":"Guttman","year":"2022","journal-title":"J. Cell Biol."},{"key":"B33","doi-asserted-by":"publisher","first-page":"e2508005","DOI":"10.4014\/jmb.2508.08005","article-title":"The ubiquitin-proteasome system in hepatitis B virus infection and hepatocarcinogenesis: viral manipulation and therapeutic targets","volume":"35","author":"Han","year":"2025","journal-title":"J. Microbiol. Biotechnol."},{"key":"B34","doi-asserted-by":"publisher","first-page":"44","DOI":"10.1186\/s40164-025-00642-7","article-title":"Hepatitis B surface antigen: carcinogenesis mechanisms and clinical implications in hepatocellular carcinoma","volume":"14","author":"Hao","year":"2025","journal-title":"Exp. Hematol. Oncol."},{"key":"B35","doi-asserted-by":"publisher","first-page":"286","DOI":"10.1016\/j.ccr.2009.12.048","article-title":"Hepatocyte IKK\u03b2\/NF-\u03baB inhibits tumor promotion and progression by preventing oxidative stress-driven STAT3 activation","volume":"17","author":"He","year":"2010","journal-title":"Cancer Cell"},{"key":"B36","doi-asserted-by":"publisher","first-page":"169","DOI":"10.1016\/j.molcel.2017.06.017","article-title":"The unfolded protein response and cell fate control","volume":"69","author":"Hetz","year":"2018","journal-title":"Mol. Cell"},{"key":"B37","doi-asserted-by":"publisher","first-page":"1219","DOI":"10.1152\/physrev.00001.2011","article-title":"The unfolded protein response: integrating stress signals through the stress sensor IRE1\u03b1","volume":"91","author":"Hetz","year":"2011","journal-title":"Physiol. Rev."},{"key":"B38","doi-asserted-by":"publisher","first-page":"421","DOI":"10.1038\/s41580-020-0250-z","article-title":"Mechanisms, regulation and functions of the unfolded protein response","volume":"21","author":"Hetz","year":"2020","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"B39","doi-asserted-by":"publisher","first-page":"2630","DOI":"10.3390\/v14122630","article-title":"Endoplasmic reticulum stress in hepatitis B virus and hepatitis C virus infection","volume":"14","author":"Hu","year":"2022","journal-title":"Viruses"},{"key":"B40","doi-asserted-by":"publisher","first-page":"101546","DOI":"10.1016\/j.aohep.2024.101546","article-title":"Genomic instabilities in hepatocellular carcinoma: biomarkers and application in immunotherapies","volume":"29","author":"Hung","year":"2024","journal-title":"Ann. Hepatology"},{"key":"B41","doi-asserted-by":"publisher","first-page":"e1232","DOI":"10.1002\/cti2.1232","article-title":"Designing the next-generation therapeutic vaccines to cure chronic hepatitis B: focus on antigen presentation, vaccine properties and effect measures","volume":"10","author":"Jansen","year":"2021","journal-title":"Clin. Transl. Immunol."},{"key":"B42","doi-asserted-by":"publisher","first-page":"229","DOI":"10.1002\/hep.24368","article-title":"Liver-specific loss of glucose-regulated protein 78 perturbs the unfolded protein response and exacerbates a spectrum of liver diseases in mice","volume":"54","author":"Ji","year":"2011","journal-title":"Hepatology"},{"key":"B43","doi-asserted-by":"publisher","first-page":"15","DOI":"10.3389\/fimmu.2024.1341985","article-title":"Single-cell RNA sequencing reveals the dynamics and heterogeneity of lymph node immune cells during acute and chronic viral infections","author":"Jin","year":"2024","journal-title":"Front. Immunol."},{"key":"B44","doi-asserted-by":"publisher","first-page":"44838","DOI":"10.1074\/jbc.M207831200","article-title":"Calnexin, calreticulin, and ERp57 cooperate in disulfide bond formation in human CD1d heavy chain","volume":"277","author":"Kang","year":"2002","journal-title":"J. Biol. Chem."},{"key":"B45","doi-asserted-by":"publisher","first-page":"102673","DOI":"10.1016\/j.dnarep.2019.102673","article-title":"Inflammation-induced DNA damage, mutations and cancer","volume":"83","author":"Kay","year":"2019","journal-title":"DNA Repair (Amst)"},{"key":"B46","doi-asserted-by":"publisher","first-page":"e1003722","DOI":"10.1371\/journal.ppat.1003722","article-title":"Hepatitis B virus disrupts mitochondrial dynamics: induces fission and mitophagy to attenuate apoptosis","volume":"9","author":"Kim","year":"2013","journal-title":"PLOS Pathog."},{"key":"B47","doi-asserted-by":"publisher","first-page":"e28","DOI":"10.4110\/in.2022.22.e28","article-title":"Evaluation of immunoproteasome-specific proteolytic activity using fluorogenic peptide substrates","volume":"22","author":"Kim","year":"2022","journal-title":"Immune Netw."},{"key":"B48","doi-asserted-by":"publisher","first-page":"1201","DOI":"10.3390\/biom14101201","article-title":"Hepatitis B virus X protein induces reactive oxygen species generation via activation of p53 in human hepatoma cells","volume":"14","author":"Kim","year":"2024","journal-title":"Biomolecules"},{"key":"B49","doi-asserted-by":"publisher","first-page":"517","DOI":"10.1016\/j.molcel.2009.01.021","article-title":"Autophagy inhibition compromises degradation of ubiquitin-proteasome pathway substrates","volume":"33","author":"Korolchuk","year":"2009","journal-title":"Mol. Cell."},{"key":"B50","doi-asserted-by":"publisher","first-page":"5","DOI":"10.3389\/fmicb.2014.00433","article-title":"Modulation of the unfolded protein response by the human hepatitis B virus","volume":"5","author":"Lazar","year":"2014","journal-title":"Front. Microbiol."},{"key":"B51","doi-asserted-by":"publisher","first-page":"1492","DOI":"10.1126\/science.1158042","article-title":"Regulation of hepatic lipogenesis by the transcription factor XBP1","volume":"320","author":"Lee","year":"2008","journal-title":"Science"},{"key":"B52","doi-asserted-by":"publisher","first-page":"44","DOI":"10.1016\/j.virusres.2006.09.011","article-title":"Hepatitis B virus X protein (HBx) activates ATF6 and IRE1-XBP1 pathways of unfolded protein response","volume":"124","author":"Li","year":"2007","journal-title":"Virus Res."},{"key":"B53","doi-asserted-by":"publisher","first-page":"6319","DOI":"10.1128\/JVI.02627-10","article-title":"Subversion of cellular autophagy machinery by hepatitis B virus for viral envelopment","volume":"85","author":"Li","year":"2011","journal-title":"J. Virology"},{"key":"B54","doi-asserted-by":"publisher","first-page":"1833","DOI":"10.1016\/j.ajpath.2018.04.015","article-title":"Impaired fasting-induced adaptive lipid droplet biogenesis in liver-specific Atg5-Deficient mouse liver is mediated by persistent nuclear factor-like 2 activation","volume":"188","author":"Li","year":"2018","journal-title":"Am. J. Pathology"},{"key":"B55","doi-asserted-by":"publisher","first-page":"851","DOI":"10.3390\/cells11050851","article-title":"Ubiquitination-proteasome system (UPS) and autophagy two main protein degradation machineries in response to cell stress","volume":"11","author":"Li","year":"2022","journal-title":"Cells"},{"key":"B56","doi-asserted-by":"publisher","first-page":"S13","DOI":"10.1002\/hep.22881","article-title":"Hepatitis B: the virus and disease","volume":"49","author":"Liang","year":"2009","journal-title":"Hepatology"},{"key":"B57","doi-asserted-by":"publisher","first-page":"641","DOI":"10.1002\/hep.31789","article-title":"Clinical implications of HBV PreS\/S mutations and the effects of PreS2 deletion on mitochondria, liver fibrosis, and cancer development","volume":"74","author":"Liang","year":"2021","journal-title":"Hepatology"},{"key":"B58","doi-asserted-by":"publisher","first-page":"101012","DOI":"10.1016\/j.jhepr.2024.101012","article-title":"Hepatitis B surface antigen expression impairs endoplasmic reticulum stress-related autophagic flux by decreasing LAMP2","volume":"6","author":"Liang","year":"2024","journal-title":"JHEP Rep."},{"key":"B59","doi-asserted-by":"publisher","first-page":"60","DOI":"10.1007\/s13238-018-0555-2","article-title":"Hepatitis B virus is degraded by autophagosome-lysosome fusion mediated by Rab7 and related components","volume":"10","author":"Lin","year":"2019","journal-title":"Protein Cell"},{"key":"B60","doi-asserted-by":"publisher","first-page":"103134","DOI":"10.1016\/j.tice.2025.103134","article-title":"Intracellullar cholesterol accumulation caused by HBV induces ATF6-mediated endoplasmic reticulum stress to trigger endoplasmic reticulophagy","volume":"98","author":"Lin","year":"2025","journal-title":"Tissue Cell"},{"key":"B61","doi-asserted-by":"publisher","first-page":"416","DOI":"10.4161\/auto.27286","article-title":"Hepatitis B virus X protein inhibits autophagic degradation by impairing lysosomal maturation","volume":"10","author":"Liu","year":"2014","journal-title":"Autophagy"},{"key":"B62","doi-asserted-by":"publisher","first-page":"16743","DOI":"10.1074\/jbc.RA120.013987","article-title":"ERAD deficiency promotes mitochondrial dysfunction and transcriptional rewiring in human hepatic cells","volume":"295","author":"Liu","year":"2020","journal-title":"J. Biol. Chem."},{"key":"B63","doi-asserted-by":"publisher","first-page":"110448","DOI":"10.1016\/j.virol.2025.110448","article-title":"ATF6-mediated mild ER stress inhibits HBV transcription and replication, which is dependent on mTOR activation","volume":"604","author":"Lu","year":"2025","journal-title":"Virology"},{"key":"B64","first-page":"3542","article-title":"Expression of PERK-eIF2\u03b1-ATF4 pathway signaling protein in the progression of hepatic fibrosis in rats","volume":"11","author":"Luo","year":"2018","journal-title":"Int. J. Clin. Exp. Pathol."},{"key":"B65","doi-asserted-by":"publisher","first-page":"7856","DOI":"10.1038\/s41467-024-52201-z","article-title":"USP26 as a hepatitis B virus-induced deubiquitinase primes hepatocellular carcinogenesis by epigenetic remodeling","volume":"15","author":"Ma","year":"2024","journal-title":"Nat. Commun."},{"key":"B66","doi-asserted-by":"publisher","first-page":"328","DOI":"10.1053\/j.gastro.2015.09.042","article-title":"Regulation of liver metabolism by autophagy","volume":"150","author":"Madrigal-Matute","year":"2016","journal-title":"Gastroenterology"},{"key":"B67","doi-asserted-by":"publisher","first-page":"235","DOI":"10.1055\/s-0039-1681032","article-title":"Endoplasmic reticulum stress in metabolic liver diseases and hepatic fibrosis","volume":"39","author":"Maiers","year":"2019","journal-title":"Semin. Liver Dis."},{"key":"B68","doi-asserted-by":"publisher","first-page":"851","DOI":"10.1016\/j.celrep.2016.06.025","article-title":"Oxidative homeostasis regulates the response to reductive endoplasmic reticulum stress through translation control","volume":"16","author":"Maity","year":"2016","journal-title":"Cell Rep."},{"key":"B69","doi-asserted-by":"publisher","first-page":"1665","DOI":"10.1016\/j.humpath.2013.01.020","article-title":"Type II ground-glass hepatocytes as a marker of hepatocellular carcinoma in chronic hepatitis B","volume":"44","author":"Mathai","year":"2013","journal-title":"Hum. Pathol."},{"key":"B70","doi-asserted-by":"publisher","first-page":"248","DOI":"10.3390\/biom15020248","article-title":"PERK-olating through cancer: a brew of cellular decisions","volume":"15","author":"Mazzolini","year":"2025","journal-title":"Biomolecules"},{"key":"B71","doi-asserted-by":"publisher","first-page":"9810","DOI":"10.1128\/JVI.79.15.9810-9820.2005","article-title":"Hepatitis B virus DNA replication is coordinated by core protein serine phosphorylation and HBx expression","volume":"79","author":"Melegari","year":"2005","journal-title":"J. Virol."},{"key":"B72","doi-asserted-by":"publisher","first-page":"4084","DOI":"10.1038\/s41467-023-39404-6","article-title":"Liver lipophagy ameliorates nonalcoholic steatohepatitis through extracellular lipid secretion","volume":"14","author":"Minami","year":"2023","journal-title":"Nat. Commun."},{"key":"B73","doi-asserted-by":"publisher","first-page":"728","DOI":"10.1016\/j.cell.2011.10.026","article-title":"Autophagy: renovation of cells and tissues","volume":"147","author":"Mizushima","year":"2011","journal-title":"Cell"},{"key":"B74","doi-asserted-by":"publisher","first-page":"662","DOI":"10.3389\/fmicb.2018.00662","article-title":"An overview of hepatitis B virus surface antigen secretion inhibitors","volume":"9","author":"Mohebbi","year":"2018","journal-title":"Front. Microbiol."},{"key":"B75","doi-asserted-by":"publisher","first-page":"1224","DOI":"10.3390\/biomedicines10061224","article-title":"Antigen load and T cell function: a challenging interaction in HBV infection","volume":"10","author":"Montali","year":"2022","journal-title":"Biomedicines"},{"key":"B76","doi-asserted-by":"publisher","first-page":"247","DOI":"10.1042\/BJ20061091","article-title":"HBx-dependent cell cycle deregulation involves interaction with cyclin E\/A-cdk2 complex and destabilization of p27Kip1","volume":"401","author":"Mukherji","year":"2007","journal-title":"Biochem. J."},{"key":"B77","doi-asserted-by":"publisher","first-page":"2846","DOI":"10.1016\/j.celrep.2016.08.026","article-title":"Hepatitis B virus X protein promotes degradation of SMC5\/6 to enhance HBV replication","volume":"16","author":"Murphy","year":"2016","journal-title":"Cell Rep."},{"key":"B78","doi-asserted-by":"publisher","first-page":"101","DOI":"10.1016\/j.cell.2007.11.023","article-title":"Dissecting the ER-associated degradation of a misfolded polytopic membrane protein","volume":"132","author":"Nakatsukasa","year":"2008","journal-title":"Cell"},{"key":"B79","doi-asserted-by":"publisher","first-page":"1250","DOI":"10.1002\/eji.200323730","article-title":"Major histocompatibility complex class II-restricted presentation of a cytosolic antigen by autophagy","volume":"33","author":"Nimmerjahn","year":"2003","journal-title":"Eur. J. Immunol."},{"key":"B80","doi-asserted-by":"publisher","first-page":"30142","DOI":"10.1074\/jbc.M115.676239","article-title":"Hepatic Xbp1 gene deletion promotes endoplasmic reticulum stress-induced liver injury and apoptosis","volume":"290","author":"Olivares","year":"2015","journal-title":"J. Biol. Chem."},{"key":"B81","doi-asserted-by":"publisher","first-page":"248","DOI":"10.1038\/ni.2808","article-title":"The unfolded-protein-response sensor IRE-1\u03b1 regulates the function of CD8\u03b1+ dendritic cells","volume":"15","author":"Osorio","year":"2014","journal-title":"Nat. Immunol."},{"key":"B82","doi-asserted-by":"publisher","first-page":"696","DOI":"10.1016\/j.tcb.2022.02.005","article-title":"Quality control of protein complex assembly by the ubiquitin-proteasome system","volume":"32","author":"Pla-Prats","year":"2022","journal-title":"Trends Cell Biol."},{"key":"B83","doi-asserted-by":"publisher","first-page":"672","DOI":"10.1006\/viro.1995.1198","article-title":"PreS and core gene heterogeneity in hepatitis B virus (HBV) genomes isolated from patients with long-lasting HBV chronic infection","volume":"208","author":"Pollicino","year":"1995","journal-title":"Virology"},{"key":"B84","doi-asserted-by":"publisher","first-page":"322","DOI":"10.1080\/10409238.2020.1784085","article-title":"Unraveling the regulatory role of endoplasmic-reticulum-associated degradation in tumor immunity","volume":"55","author":"Qin","year":"2020","journal-title":"Crit. Rev. Biochem. Mol. Biol."},{"key":"B85","doi-asserted-by":"publisher","first-page":"5632","DOI":"10.3390\/cancers15235632","article-title":"Targeting proteasomes and the MHC class I antigen presentation machinery to treat cancer, infections and age-related diseases","volume":"15","author":"Rana","year":"2023","journal-title":"Cancers (Basel)"},{"key":"B86","doi-asserted-by":"publisher","first-page":"1393","DOI":"10.1152\/physrev.00038.2021","article-title":"ER-phagy: mechanisms, regulation, and diseases connected to the lysosomal clearance of the endoplasmic reticulum","volume":"102","author":"Reggiori","year":"2022","journal-title":"Physiol. Rev."},{"key":"B87","doi-asserted-by":"publisher","first-page":"483","DOI":"10.1128\/JVI.01779-06","article-title":"Role of immunoproteasome catalytic subunits in the immune response to hepatitis B virus","volume":"81","author":"Robek","year":"2007","journal-title":"J. Virol."},{"key":"B88","doi-asserted-by":"publisher","first-page":"533","DOI":"10.2174\/1566524016666160523143937","article-title":"The role of the PERK\/eIF2\u03b1\/ATF4\/CHOP signaling pathway in tumor progression during endoplasmic reticulum stress","volume":"16","author":"Rozpedek","year":"2016","journal-title":"Curr. Mol. Med."},{"key":"B89","doi-asserted-by":"publisher","first-page":"10147","DOI":"10.1038\/s41598-019-46657-z","article-title":"LC3-positive structures are prominent in autophagy-deficient cells","volume":"9","author":"Runwal","year":"2019","journal-title":"Sci. Rep."},{"key":"B90","doi-asserted-by":"publisher","first-page":"1403","DOI":"10.1016\/j.jhep.2016.02.004","article-title":"IL-6 pathway in the liver: from physiopathology to therapy","volume":"64","author":"Schmidt-Arras","year":"2016","journal-title":"Hepatol"},{"key":"B91","doi-asserted-by":"publisher","first-page":"e00424","DOI":"10.1128\/jvi.00424-24","article-title":"The impact of HBx protein on mitochondrial dynamics and associated signaling pathways strongly depends on the hepatitis B virus genotype","volume":"98","author":"Schollmeier","year":"2024","journal-title":"J. Virology"},{"key":"B92","doi-asserted-by":"publisher","first-page":"53","DOI":"10.1016\/j.jhep.2021.08.010","article-title":"HBx-induced degradation of Smc5\/6 complex impairs homologous recombination-mediated repair of damaged DNA","volume":"76","author":"Sekiba","year":"2022","journal-title":"J. Hepatol."},{"key":"B93","doi-asserted-by":"publisher","first-page":"556","DOI":"10.1016\/j.cmet.2009.04.009","article-title":"The IRE1alpha-XBP1 pathway of the unfolded protein response is required for adipogenesis","volume":"9","author":"Sha","year":"2009","journal-title":"Cell Metab."},{"key":"B94","doi-asserted-by":"publisher","first-page":"796","DOI":"10.1016\/S2468-1253(22)00124-8","article-title":"Global, regional, and national burden of hepatitis B. 1990\u20132019: a systematic analysis for the global burden of disease study 2019","volume":"7","author":"Sheena","year":"2022","journal-title":"Lancet Gastroenterol. Hepatol."},{"key":"B95","doi-asserted-by":"publisher","first-page":"99","DOI":"10.1016\/s1534-5807(02)00203-4","article-title":"ER stress regulation of ATF6 localization by dissociation of BiP\/GRP78 binding and unmasking of golgi localization signals","volume":"3","author":"Shen","year":"2002","journal-title":"Dev. Cell"},{"key":"B96","doi-asserted-by":"publisher","first-page":"5013","DOI":"10.3390\/cancers14205013","article-title":"Immunotherapeutic approaches for treating hepatocellular carcinoma","volume":"14","author":"Shen","year":"2022","journal-title":"Cancers (Basel)"},{"key":"B97","doi-asserted-by":"publisher","first-page":"15","DOI":"10.1167\/iovs.62.12.15","article-title":"Mitochondrial ROS induced lysosomal dysfunction and autophagy impairment in an animal model of congenital hereditary endothelial dystrophy","volume":"62","author":"Shyam","year":"2021","journal-title":"Invest Ophthalmol. Vis. Sci."},{"key":"B98","doi-asserted-by":"publisher","first-page":"323","DOI":"10.1016\/j.semcancer.2013.05.005","article-title":"Modulation of the autophagy pathway by human tumor viruses","volume":"23","author":"Silva","year":"2013","journal-title":"Semin. Cancer Biol."},{"key":"B99","doi-asserted-by":"publisher","first-page":"149","DOI":"10.1016\/0165-2478(96)02531-x","article-title":"Markedly decreased expression of TAP1 and LMP2 genes in HLA class I-deficient human tumor cell lines","volume":"50","author":"Singal","year":"1996","journal-title":"Immunol. Lett."},{"key":"B100","doi-asserted-by":"publisher","first-page":"4383","DOI":"10.1073\/pnas.0911373107","article-title":"The early autophagic pathway is activated by hepatitis B virus and required for viral DNA replication","volume":"107","author":"Sir","year":"2010","journal-title":"Proc. Natl. Acad. Sci."},{"key":"B101","doi-asserted-by":"publisher","first-page":"1169","DOI":"10.1111\/j.1440-1746.2008.05348.x","article-title":"Ground glass hepatocytes contain pre-S mutants and represent preneoplastic lesions in chronic hepatitis B virus infection","volume":"23","author":"Su","year":"2008","journal-title":"J. Gastroenterol. Hepatol."},{"key":"B102","doi-asserted-by":"publisher","first-page":"751","DOI":"10.1186\/s12967-024-05552-6","article-title":"Strategies to enhance the therapeutic efficacy of anti-PD-1 antibody, anti-PD-L1 antibody and anti-CTLA-4 antibody in cancer therapy","volume":"22","author":"Su","year":"2024","journal-title":"J. Transl. Med."},{"key":"B103","doi-asserted-by":"publisher","first-page":"3171","DOI":"10.1083\/jcb.201906047","article-title":"Protein quality control in the secretory pathway","volume":"218","author":"Sun","year":"2019","journal-title":"J. Cell Biol."},{"key":"B104","doi-asserted-by":"publisher","first-page":"795","DOI":"10.1101\/gad.2016211","article-title":"Autophagy-deficient mice develop multiple liver tumors","volume":"25","author":"Takamura","year":"2011","journal-title":"Genes Dev."},{"key":"B105","doi-asserted-by":"publisher","first-page":"327","DOI":"10.1016\/j.devcel.2018.04.023","article-title":"The UPR activator ATF6 responds to proteotoxic and lipotoxic stress by distinct mechanisms","volume":"46","author":"Tam","year":"2018","journal-title":"Dev. Cell"},{"key":"B106","doi-asserted-by":"publisher","first-page":"3275","DOI":"10.1128\/JVI.03545-14","article-title":"The interface between hepatitis B virus capsid proteins affects self-assembly, pregenomic RNA packaging, and reverse transcription","volume":"89","author":"Tan","year":"2015","journal-title":"J. Virol."},{"key":"B107","doi-asserted-by":"publisher","first-page":"60","DOI":"10.1002\/hep.22581","article-title":"Hepatitis B virus X protein sensitizes cells to starvation\u2010induced autophagy via up\u2010regulation of beclin 1 expression","volume":"49","author":"Tang","year":"2009","journal-title":"Hepatology"},{"key":"B108","doi-asserted-by":"publisher","first-page":"433","DOI":"10.1038\/sj.emboj.7601963","article-title":"Fission and selective fusion govern mitochondrial segregation and elimination by autophagy","volume":"27","author":"Twig","year":"2008","journal-title":"EMBO J."},{"key":"B109","doi-asserted-by":"publisher","first-page":"929","DOI":"10.1097\/HEP.0000000000000335","article-title":"HBV with precore and basal core promoter mutations exhibits a high replication phenotype and causes ER stress-mediated cell death in humanized liver chimeric mice","volume":"78","author":"Uchida","year":"2023","journal-title":"Hepatology"},{"key":"B110","doi-asserted-by":"publisher","first-page":"1081","DOI":"10.1126\/science.1209038","article-title":"The unfolded protein response: from stress pathway to homeostatic regulation","volume":"334","author":"Walter","year":"2011","journal-title":"Science."},{"key":"B111","doi-asserted-by":"publisher","first-page":"683","DOI":"10.1111\/j.1349-7006.2006.00235.x","article-title":"Hepatitis B virus pre-S mutants, endoplasmic reticulum stress and hepatocarcinogenesis","volume":"97","author":"Wang","year":"2006","journal-title":"Cancer Sci."},{"key":"B112","doi-asserted-by":"publisher","first-page":"974","DOI":"10.1002\/hep.30248","article-title":"Hepatitis B virus induces autophagy to promote its replication by the axis of miR\u2010192\u20103p\u2010XIAP through NF kappa B signaling","volume":"69","author":"Wang","year":"","journal-title":"Hepatology"},{"key":"B113","doi-asserted-by":"publisher","first-page":"e1007541","DOI":"10.1371\/journal.ppat.1007541","article-title":"p62-mediated selective autophagy endows virus-transformed cells with insusceptibility to DNA damage under oxidative stress","volume":"15","author":"Wang","year":"","journal-title":"PLoS Pathog."},{"key":"B114","doi-asserted-by":"publisher","first-page":"438","DOI":"10.1002\/hep.32178","article-title":"Endoplasmic reticulum stress promotes HBV production by enhancing use of the autophagosome\/multivesicular body axis","volume":"75","author":"Wang","year":"","journal-title":"Hepatology"},{"key":"B115","doi-asserted-by":"publisher","first-page":"312","DOI":"10.1016\/j.jhep.2022.02.031","article-title":"Role of XBP1 in regulating the progression of non-alcoholic steatohepatitis","volume":"77","author":"Wang","year":"","journal-title":"J. Hepatol."},{"key":"B116","doi-asserted-by":"publisher","first-page":"1025","DOI":"10.1038\/s41586-025-09539-1","article-title":"Proteotoxic stress response drives T cell exhaustion and immune evasion","volume":"647","author":"Wang","year":"2025","journal-title":"Nature"},{"key":"B117","doi-asserted-by":"publisher","first-page":"1799","DOI":"10.3390\/ijms22041799","article-title":"Endoplasmic reticulum stress signaling and the pathogenesis of hepatocarcinoma","volume":"22","author":"Wei","year":"2021","journal-title":"Int. J. Mol. Sci."},{"key":"B118","doi-asserted-by":"publisher","first-page":"2563079","DOI":"10.1080\/22221751.2025.2563079","article-title":"Mitochondrial respiratory chain regulates HBV clearance through dual modulation of lysosomal acidification","volume":"14","author":"Wei","year":"2025","journal-title":"Emerg. Microbes Infect."},{"key":"B119","doi-asserted-by":"publisher","first-page":"446","DOI":"10.4049\/jimmunol.2300263","article-title":"Balanced epigenetic regulation of MHC class I expression in tumor cells by the histone ubiquitin modifiers BAP1 and PCGF1","volume":"212","author":"Wijdeven","year":"2024","journal-title":"J. Immunol."},{"key":"B120","doi-asserted-by":"publisher","first-page":"533","DOI":"10.1002\/hep.29871","article-title":"Dual role for inositol\u2010requiring enzyme 1\u03b1 in promoting the development of hepatocellular carcinoma during diet\u2010induced obesity in mice","volume":"68","author":"Wu","year":"2018","journal-title":"Hepatology"},{"key":"B121","doi-asserted-by":"publisher","first-page":"112005","DOI":"10.1016\/j.biopha.2021.112005","article-title":"Endoplasmic reticulum stress: multiple regulatory roles in hepatocellular carcinoma","volume":"142","author":"Wu","year":"2021","journal-title":"Biomed. Pharmacother."},{"key":"B122","doi-asserted-by":"publisher","first-page":"938","DOI":"10.1038\/s41419-019-2175-z","article-title":"Mitochondria ubiquitin ligase, MARCH5 resolves hepatitis B virus X protein aggregates in the liver pathogenesis","volume":"10","author":"Yoo","year":"2019","journal-title":"Cell Death and Dis."},{"key":"B123","doi-asserted-by":"publisher","first-page":"829923","DOI":"10.3389\/fimmu.2022.829923","article-title":"Regulation of pattern-recognition receptor signaling by HBX during hepatitis B virus infection","volume":"13","author":"You","year":"2022","journal-title":"Front. Immunol."},{"key":"B124","first-page":"1179","article-title":"The roles of E3 ligases in hepatocellular carcinoma","volume":"12","author":"Yu","year":"2022","journal-title":"Am. J. Cancer Res."},{"key":"B125","doi-asserted-by":"publisher","first-page":"13","DOI":"10.3389\/fimmu.2022.1032819","article-title":"Exploring the molecular mechanism of hepatitis virus inducing hepatocellular carcinoma by microarray data and immune infiltrates analysis","author":"Zhang","year":"","journal-title":"Front. Immunol."},{"key":"B126","doi-asserted-by":"publisher","first-page":"132","DOI":"10.1038\/s41419-022-04593-3","article-title":"The regulation, function, and role of lipophagy, a form of selective autophagy, in metabolic disorders","volume":"13","author":"Zhang","year":"","journal-title":"Cell Death and Dis."},{"key":"B127","doi-asserted-by":"publisher","first-page":"1233","DOI":"10.1038\/s41388-024-02988-4","article-title":"Targeting the IRE1\u03b1-XBP1s axis confers selective vulnerability in hepatocellular carcinoma with activated wnt signaling","volume":"43","author":"Zhang","year":"2024","journal-title":"Oncogene"},{"key":"B128","doi-asserted-by":"publisher","first-page":"15","DOI":"10.3389\/fonc.2025.1691719","article-title":"Rewiring tumor visibility: the immunopeptidome as a dynamic interface between antigen processing, microenvironmental stress, and immune recognition","author":"Zhao","year":"2025","journal-title":"Front. Oncol."},{"key":"B129","doi-asserted-by":"publisher","first-page":"13","DOI":"10.3389\/fcimb.2023.1206720","article-title":"Immune response and treatment targets of chronic hepatitis B virus infection: innate and adaptive immunity","author":"Zheng","year":"2023","journal-title":"Front. Cell. Infect. Microbiol."},{"key":"B130","doi-asserted-by":"publisher","first-page":"35","DOI":"10.1038\/s41392-024-02075-w","article-title":"Hepatocellular carcinoma: signaling pathways and therapeutic advances","volume":"10","author":"Zheng","year":"2025","journal-title":"Signal Transduct. Target. Ther."},{"key":"B131","doi-asserted-by":"publisher","first-page":"1127071","DOI":"10.3389\/fimmu.2023.1127071","article-title":"Mechanisms of drug resistance to immune checkpoint inhibitors in non-small cell lung cancer","volume":"14","author":"Zhou","year":"2023","journal-title":"Front. Immunol."},{"key":"B132","doi-asserted-by":"publisher","first-page":"107332","DOI":"10.1016\/j.phrs.2024.107332","article-title":"Regulation mechanism of endoplasmic reticulum stress on metabolic enzymes in liver diseases","volume":"207","author":"Zhou","year":"2024","journal-title":"Pharmacol. Res."},{"key":"B133","doi-asserted-by":"publisher","first-page":"105603","DOI":"10.1016\/j.phrs.2021.105603","article-title":"Mitochondrial unfolded protein response: a novel pathway in metabolism and immunity","volume":"168","author":"Zhu","year":"2021","journal-title":"Pharmacol. Res."}],"container-title":["Frontiers in Pharmacology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2026.1786614\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,10]],"date-time":"2026-04-10T06:06:00Z","timestamp":1775801160000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2026.1786614\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,4,10]]},"references-count":133,"alternative-id":["10.3389\/fphar.2026.1786614"],"URL":"https:\/\/doi.org\/10.3389\/fphar.2026.1786614","relation":{},"ISSN":["1663-9812"],"issn-type":[{"value":"1663-9812","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,4,10]]},"article-number":"1786614"}}