Abstract
Background: Extracellular vesicles (EVs), including exosomes, microvesicles, and apoptotic bodies, are nanoscale mediators of intercellular communication critical to liver physiology and pathology. These vesicles encapsulate diverse biomolecules proteins, lipids, and nucleic acids that mirror their cells of origin and modulate recipient cell function. Liver diseases such as metabolic dysfunction-associated steatotic liver disease (MASLD), alcoholic liver disease (ALD), viral hepatitis, fibrosis, cirrhosis, and hepatocellular carcinoma (HCC) represent significant
global health burdens with diagnostic and therapeutic challenges, especially at advanced stages. The genetic basis of liver diseases, including polymorphisms in PNPLA3, TM6SF2, and HSD17B13, significantly influences disease susceptibility and progression, with emerging evidence suggesting these genetic variants may also modulate EV cargo composition and release patterns.
Purpose: This review aims to comprehensively dissect the biogenesis, molecular composition, and pathophysiological roles of EVs in liver diseases, highlighting their diagnostic and therapeutic potential. It emphasizes the potential integration of genomic insights with EV biology, exploring how genetic variants might influence EV-mediated pathogenesis and the potential for EV-based approaches to complement nextgeneration sequencing (NGS) and genomic diagnostics in precision hepatology.
Main Body: We detail the cellular mechanisms underpinning EV formation in hepatocytes and non-parenchymal liver cells, including ESCRTdependent and -independent pathways, and their modulation by pathological stimuli such as inflammation and oxidative stress. The potential influence of genetic variants on EV biogenesis and cargo loading is explored, with particular focus on how polymorphisms in genes such as PNPLA3 I148M and TM6SF2 E167K might affect hepatocyte EV release in metabolic liver disease. The molecular cargo of EVs encompassing microRNAs (e.g., miR-122, miR-21), proteins (e.g., TGF-β, CTGF), and lipids (e.g., ceramides) plays a pivotal role in mediating liver inflammation, fibrogenesis, immune modulation, and oncogenesis. Distinct EV profiles may correlate with genetic risk factors and disease stages in MASLD, ALD, viral hepatitis, fibrosis, and HCC, potentially offering promising biomarker candidates that could complement genomic testing for early detection, prognosis, and treatment monitoring. Furthermore, engineered EVs demonstrate therapeutic efficacy in delivering antifibrotic agents and immunomodulators, while targeting EV biogenesis and uptake pathways presents novel treatment strategies. The theoretical integration of EV profiling with genomic data may enhance risk stratification and enable personalized therapeutic approaches in inherited liver disorders. Challenges in EV isolation, standardization, and clinical translation are acknowledged alongside ongoing clinical trials assessing EV-based diagnostics and therapeutics.
Conclusion: EVs represent a transformative frontier in hepatology, integrating molecular insights into liver disease pathogenesis with innovative diagnostic and therapeutic avenues. The potential convergence of EV biology with genomic medicine offers unprecedented opportunities for precision hepatology, where EV signatures informed by genetic variants could guide personalized diagnostic and therapeutic strategies. Future research must focus on standardizing methodologies, validating multi-omics EV signatures in the context of genetic backgrounds, and overcoming translational hurdles to fully harness EVs' potential in precision liver medicine.
Keywords
Extracellular vesicles, Liver diseases, Biomarkers, MicroRNA, Hepatic fibrosis, Genomic medicine, Genetic variants, Precision hepatology