Emerging Biomarker Potential of Extracellular Vesicle-Enclosed MicroRNAs for Liver Fibrosis Detection

Abstract

Liver fibrosis is a frequent pathological outcome of long-term liver diseases, arising from sustained damage to the liver. Two main types of liver damage can trigger fibrotic progression: hepatocellular injury, often caused by viral infections, alcohol, or metabolic disorders, and cholestatic injury, associated with impaired bile flow due to autoimmune or congenital conditions. Despite diverse etiologies, liver fibrosis exhibits conserved biological processes, including hepatocyte death, chronic inflammation, disruption of epithelial or endothelial barriers, and excessive deposition of extracellular matrix (ECM) components. These coordinated events reflect the complex interplay among parenchymal damage, immune activation, and fibrogenic signaling pathways. If unresolved, fibrosis may progress to cirrhosis, liver failure, or hepatocellular carcinoma. In the pursuit of non-invasive biomarkers for early detection and monitoring of fibrosis, extracellular vesicles (EVs) have garnered significant attention. Among the diverse cargoes within EVs, microRNAs (miRNAs) have emerged as particularly promising due to their stability, disease-specific expression patterns, and involvement in fibrogenic signaling. This review explores the role of EV-associated miRNAs in liver fibrosis, highlighting key candidates implicated in hepatocellular and cholestatic injury and their clinical potential as diagnostic and prognostic biomarkers, with special focus on MAFLD/MASH, primary sclerosing cholangitis, primary biliary cholangitis, and biliary atresia as representatives.

Keywords: biomarkers; chronic liver diseases; extracellular vesicles; fibrosis; microRNAs.

Figure 1

Liver cells release EVs to perpetuate fibrotic signals. Following damage to hepatocytes (hepatocellular) or cholangiocytes (biliary), all hepatic cell types react by releasing growth factors, cytokines, or EVs into the secretome, which lead to the dedifferentiation of LSECs followed by activation of HSCs or fibroblasts and dysregulated production of ECM. Infiltrating inflammatory cells also contribute to liver fibrosis with their load of secreted factors.

Figure 2

Mouse models of human biliary tract diseases. Representative models of biliary damage caused by bile duct obstruction, genetic defects, or exposure to hepatotoxins are shown, with clinical translatability regarding cancer and gallstones, progressive familial intrahepatic cholestasis type 3 (PFIC3), primary sclerosing cholangitis (PSC) and biliary atresia, respectively, in humans. BDL—bile duct ligation; Mdr2—multidrug resistance 2 (Abcb4); DDC—3,5-diethoxycarbonyl-1,4 dihydrocollidine.