From Genomic Instability to Epigenetic Signatures: The Evolving Landscape of Circulating Cell‐free DNA in Metabolic Dysfunction‐Associated Steatotic Liver Disease

Metabolic dysfunction-associated steatotic liver disease (MASLD) represents a leading global health burden, yet its diagnosis and staging rely heavily on invasive liver biopsies. Liquid biopsy, utilizing circulating cell-free DNA (cfDNA), offers a promising noninvasive alternative to capture hepatic genomic instability. This review consolidates current knowledge on cfDNA biomarkers in MASLD, moving from established quantitative metrics to emerging epigenetic insights. The role of mitochondrial DNA copy number (mtDNAcn) is examined as a dynamic marker of oxidative stress, highlighting its biphasic response: compensatory upregulation in early disease versus depletion in advanced fibrosis. Furthermore, key nuclear copy number variations (CNVs) specifically the XPO4 duplication (13q12.11), CES1 deletion (16q12.2), and ACOT1 deletion (14q24.3) are discussed regarding their mechanistic drivers of fibrogenesis and lipid metabolism dysregulation. Addressing the complexity of MASLD pathogenesis, the discussion extends to emerging multi-modal metrics, including DNA methylation and fragmentomics. These modalities offer superior specificity by tracing the "tissue of origin" and distinguishing apoptotic from necrotic fragmentation patterns, effectively addressing the diagnostic challenges posed by the "burnout" phenomenon in advanced cirrhosis. Finally, critical future directions are outlined, emphasizing the necessity for standardized pre-analytical protocols and the integration of multi-omics data with machine learning. This comprehensive approach will shed light on the transition cfDNA from a research tool to a precise clinical instrument for early risk stratification and therapeutic monitoring.