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This study focused on miR-4461, which is encoded within the intronic region of PCBD2 gene, and investigated its role in HBV-derived HCC.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>miR-4461 expression was examined in HBV-expressing hepatoma cell lines and in HBV-infected primary human hepatocytes. Functional analysis evaluated the effects of miR-4461 overexpression or inhibition on hepatocyte proliferation. Candidate targets were screened, and fibrinogen alpha chain (FGA) was tested for regulation by miR-4461. Circulating miR-4461 and plasma FGA were measured in patients with chronic viral hepatitis, including those with HBV-related HCC; in the HBV-HCC cohort, FGA was also assessed before and after surgical tumor resection.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>miR-4461 expression was significantly reduced in HBV-expressing hepatoma cells and HBV-infected primary hepatocytes. Overexpression of miR-4461 inhibited hepatocyte proliferation, whereas its inhibition enhanced proliferation, indicating a tumor-suppressive function. FGA was identified as a downstream target; in hepatoma cells, FGA protein levels were regulated by miR-4461. Clinically, circulating miR-4461 levels were significantly lower in HBV-infected individuals, particularly in those with HBV-related HCC. In contrast, plasma FGA protein levels were markedly elevated in HBV-related HCC and decreased significantly after tumor resection.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>These findings suggest a novel regulatory axis in HBV-associated HCC involving HBV-induced suppression of miR-4461 and subsequent upregulation of FGA. Both miR-4461 and FGA were associated with disease status, supporting their potential utility as biomarkers or therapeutic targets in HBV-derived HCC.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1007\/s00535-026-02433-1","type":"journal-article","created":{"date-parts":[[2026,4,30]],"date-time":"2026-04-30T17:53:02Z","timestamp":1777571582000},"page":"1146-1158","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["HBV-induced miR-4461 downregulation correlates with elevated fibrinogen alpha chain expression in hepatocellular carcinoma"],"prefix":"10.1007","volume":"61","author":[{"given":"Masatake","family":"Kanai","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aiko","family":"Sakai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomoko","family":"Date","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoshihiko","family":"Aoki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fuminori","family":"Mihara","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takashi","family":"Kokudo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fuyuki","family":"Inagaki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nobuyuki","family":"Takemura","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Norihiro","family":"Kokudo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9084-7197","authenticated-orcid":false,"given":"Masaya","family":"Sugiyama","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,4,30]]},"reference":[{"key":"2433_CR1","unstructured":"Organization WH. 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