{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T00:05:46Z","timestamp":1790208346581,"version":"4.1.0"},"reference-count":206,"publisher":"MDPI AG","issue":"17","license":[{"start":{"date-parts":[[2026,8,24]],"date-time":"2026-08-24T00:00:00Z","timestamp":1787529600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Int. J. Mol. Sci.","IJMS"],"abstract":"<jats:p>Chronic hepatitis B virus (CHB) infection remains a major cause of hepatocellular carcinoma (HCC), yet the premalignant microenvironment that links to HBV-associated HCC (HBV-HCC) is still poorly defined. This review synthesizes evidence that HBV-infected hepatocytes function as signaling hubs that, through microRNA (miRNA)-regulated crosstalk with Kupffer cells, liver sinusoidal endothelial cells, hepatic stellate cells and cancer-associated fibroblasts (CAFs), progressively remodel the liver from an antiviral tissue into a premalignant and early tumor microenvironment. Across the HBV-HCC continuum, a core set of dysregulated miRNAs, including miR-21, miR-29a\/b, miR-122, miR-146a, miR-155, miR-200a, miR-126, miR-210 and the miR-130\/301 family, coordinates transition from innate antiviral responses to HSC activation, extracellular matrix deposition, mechanotransduction, angiogenesis, chronic inflammation and cancer-associated CAF programing. By mapping these stage-specific miRNA networks onto acute infection, CHB, early fibrogenesis, advanced fibrosis and CAF-rich dysplastic states, the review reframes HBV-HCC pathogenesis as a sequence of miRNA-guided hepatocyte\u2013stromal states rather than a purely hepatocyte-intrinsic process. This perspective suggests that composite, cell-type-resolved miRNA signatures in serum or liver tissue could serve as biomarkers for identifying CHB patients who are entering a premalignant microenvironment before conventional surveillance markers become abnormal. It further highlights miRNA hubs that couple antiviral, fibrogenic, angiogenic and CAF-associated signaling as potential therapeutic targets for reprograming the HBV-driven premalignant microenvironment, with the long-term goal of intercepting HBV-HCC development at earlier, microenvironmentally defined stages.<\/jats:p>","DOI":"10.3390\/ijms27177581","type":"journal-article","created":{"date-parts":[[2026,8,24]],"date-time":"2026-08-24T17:20:28Z","timestamp":1787592028000},"page":"7581","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["MicroRNA Control of Hepatocyte\u2013Stromal Crosstalk in the Early Premalignant Microenvironment of HBV-Associated HCC"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8912-9059","authenticated-orcid":false,"given":"Kurt","family":"Sartorius","sequence":"first","affiliation":[{"name":"School of Laboratory Medicine and Molecular Sciences, University of KwaZulu-Natal (UKZN), Durban 4041, South Africa"},{"name":"Africa Hepatobiliary Cancer Consortium (AHPBCC), Mayo Clinic, Jacksonville, MN 55902, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6006-3765","authenticated-orcid":false,"given":"Anna","family":"Kramvis","sequence":"additional","affiliation":[{"name":"Hepatitis Virus Diversity Research Unit, University of the Witwatersrand, Johannesburg 2000, South Africa"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4649-4133","authenticated-orcid":false,"given":"Anil","family":"Chuturgoon","sequence":"additional","affiliation":[{"name":"School of Laboratory Medicine and Molecular Sciences, University of KwaZulu-Natal (UKZN), Durban 4041, South Africa"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,24]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Al-Busafi, S.A., and Alwassief, A. 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