Evaluation of cell free DNA methylation as a biomarker to differentiate different liver diseases

INTRODUCTION: A major challenge in many liver diseases is the lack of highly sensitive, specific, and minimally invasive biomarkers. Cell-free DNA (cfDNA) methylation compensates for the limitations of existing biomarkers and exhibits substantial clinical application potential in a variety of liver diseases, notably hepatocellular carcinoma (HCC). A systematic literature search was conducted in the PubMed, Web of Science Core Collection, and Cochrane Library databases from 1 January 2000, to 31 December 2025. AREAS COVERED: This article systematically explores the value of cfDNA methylation as a biomarker in diverse liver diseases, covering metabolic-associated fatty liver disease, hepatitis B virus-related liver disease, autoimmune liver diseases, cholestatic liver disease, graft injury after liver transplantation, acute-on-chronic liver failure, and HCC. EXPERT OPINION: cfDNA methylation is a promising biomarker. In various liver diseases, particularly HCC, its diagnostic efficacy not only outperforms some traditional biomarkers but also complements others. Coupled with its minimally invasive nature, this supports personalized treatment strategies and long-term disease management. However, current research lacks standardized protocols. Future efforts should therefore focus on establishing unified standards for technical procedures, data analysis, and clinical interpretation to accelerate its translation from basic research to clinical application.