MicroRNA Control of Hepatocyte–Stromal Crosstalk in the Early Premalignant Microenvironment of HBV-Associated HCC

Abstract

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–stromal 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.