Mitochondrial echoes in the bloodstream: decoding ccf-mtDNA for the early detection and prognosis of hepatocellular carcinoma.

Hepatocellular carcinoma (HCC), the most common primary liver cancer, remains a major global health burden due to its high recurrence, late diagnosis, and limited prognostic tools. While imaging and treatment modalities have advanced, there is an urgent need for reliable, noninvasive biomarkers to facilitate early detection, therapeutic monitoring, and outcome prediction. Circulating cell-free mitochondrial DNA (ccf-mtDNA) has emerged as a promising candidate biomarker, attributed to its unique biological properties, including high copy number, circular configuration, and resistance to degradation. Ccf-mtDNA enters the circulation via diverse mechanisms such as mitochondrial damage, extrusion through extracellular vesicles, and neutrophil extracellular traps, all of which are prevalent in the inflammatory and hypoxic tumor microenvironment of HCC. Accumulating evidence links alterations in ccf-mtDNA levels, sequence variants, and fragmentomic profiles with tumor burden, treatment response, and overall survival. Notably, its potential utility has been demonstrated in patients receiving locoregional therapies such as transarterial chemoembolization. However, variability in findings across studies, lack of methodological consensus, and confounding effects from liver inflammation or injury pose significant barriers to clinical translation. This review provides a comprehensive overview of the origins, biological significance, and clinical applicability of ccf-mtDNA in HCC, and explores emerging interest in mitochondrial DNA encapsulated in extracellular vesicles as a novel diagnostic tool. Addressing current challenges through assay standardization and validation in larger, stratified cohorts will be pivotal for its integration into precision oncology frameworks.