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Circulating histones as potential biomarkers of MASLD-MASH-HCC progression
Desislava K Tsoneva1,2, Diana Buzova3, Salvatore Daniele Bianco4
1Department of Medical Genetics, Medical University of Varna, Varna, Bulgaria.
Epigenomics
|January 5, 2026
Summary
Plasma histones H2A and H4 show promise as biomarkers for liver disease progression. These findings could lead to rapid methods for distinguishing metabolic dysfunction-associated steatohepatitis (MASH) and predicting hepatocellular carcinoma (HCC) risk.
Area of Science:
- Biochemistry
- Oncology
- Hepatology
Background:
- Metabolic dysfunction-associated steatotic liver disease (MASLD) and its inflammatory form, MASH, require reliable biomarkers for risk stratification.
- Patients with MASH are at increased risk for developing hepatocellular carcinoma (HCC).
- Current methods for identifying at-risk patients are insufficient, necessitating novel biomarker discovery.
Purpose of the Study:
- To investigate the potential of circulating histones as biomarkers for predicting liver disease progression in MASLD and MASH.
- To evaluate the ability of plasma histone levels to discriminate between MASH and non-MASH patients.
- To assess the utility of histones in predicting the risk of HCC development.
Main Methods:
- Plasma histone levels were quantified using imaging flow cytometry.
- The study included patients with MASLD, MASH, HCC, and healthy controls.
- Machine-learning analysis was employed to identify predictive patterns.
Main Results:
- Elevated levels of H2A, H3, and various histone complexes were observed in MASLD/MASH and HCC patients compared to controls.
- Specific histone patterns (decreased macroH2A1.2/H2B/H3/H4 in MASLD/MASH; increased in HCC) differentiated disease states.
- Reduced H4 levels distinguished MASH from non-MASH, and decreased H2A and H4 levels were associated with MASH in machine-learning models.
Conclusions:
- Plasma histones H2A and H4 emerge as novel biomarkers for liver disease progression in MASLD and MASH.
- Imaging flow cytometry-based histone analysis offers a rapid method for differentiating MASH from non-MASH.
- Histone biomarkers hold potential for predicting HCC development risk in patients with liver disease.
