{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,28]],"date-time":"2026-07-28T14:22:52Z","timestamp":1785248572845,"version":"3.55.0"},"reference-count":49,"publisher":"Wiley","issue":"12","license":[{"start":{"date-parts":[[2023,12,18]],"date-time":"2023-12-18T00:00:00Z","timestamp":1702857600000},"content-version":"vor","delay-in-days":17,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100008903","name":"Ministry of Health and Welfare","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100008903","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100011912","name":"Taipei Veterans General Hospital","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100011912","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Journal of Medical Virology"],"published-print":{"date-parts":[[2023,12]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Hepatitis B virus (HBV) hijacks autophagy for its replication. Nucleos(t)ide analogs (NUCs) treatment suppressed HBV replication and reduced hepatocellular carcinoma (HCC) incidence. However, the use of NUCs in chronic hepatitis B (CHB) patients with normal or minimally elevated serum alanine aminotransferase (ALT) levels is still debated. Animal models are crucial for studying the unanswered issue and evaluating new therapies. MicroRNA\u2010122 (miR\u2010122), which regulates fatty acid and cholesterol metabolism, is downregulated during hepatitis and HCC progression. The reciprocal inhibition of miR\u2010122 with HBV highlights its role in HCC development as a tumor suppressor. By crossbreeding HBV\u2010transgenic mice with miR\u2010122 knockout mice, we generated a hybrid mouse model with a high incidence of HCC up to 89% and normal ALT levels before HCC. The model exhibited early\u2010onset hepatic steatosis, progressive liver fibrosis, and impaired late\u2010phase autophagy. Metabolomics and microarray analysis identified metabolic signatures, including dysregulation of lipid metabolism, inflammation, genomic instability, the Warburg effect, reduced TCA cycle flux, energy deficiency, and impaired free radical scavenging. Antiviral treatment reduced HCC incidence in hybrid mice by approximately 30\u201335% compared to untreated mice. This effect was linked to the activation of ER stress\u2010responsive transcription factor ATF4, clearance of autophagosome cargo p62, and suppression of the CHOP\u2010mediated apoptosis pathway. In summary, this study suggests that despite minimal ALT elevation, HBV replication can lead to liver injury. Endoplasmic reticulum stress, reduced miR\u2010122 levels, mitochondrial and metabolic dysfunctions, blocking protective autophagy resulting in p62 accumulation, apoptosis, fibrosis, and HCC. Antiviral may improve the above\u2010mentioned pathogenesis through HBV suppression.<\/jats:p>","DOI":"10.1002\/jmv.29325","type":"journal-article","created":{"date-parts":[[2023,12,18]],"date-time":"2023-12-18T10:14:39Z","timestamp":1702894479000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Antiviral therapy reduces hepatocellular carcinoma through suppressing hepatitis B virus replication may improve ER stress, mitochondrial and metabolic dysfunctions and decrease p62 in hybridized mice with single HBV transgene and miR\u2010122"],"prefix":"10.1002","volume":"95","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3774-3329","authenticated-orcid":false,"given":"Yuh\u2010Jin","family":"Liang","sequence":"first","affiliation":[{"name":"Translational Research Division, Medical Research Department Taipei Veterans General Hospital Taipei Taiwan, ROC"},{"name":"Cancer Progression Research Center National Yang Ming 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