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This is an early access version, the complete PDF, HTML, and XML versions will be available soon.
Article

Association Between Active DNA Demethylation and Liver Fibrosis in Individuals with Metabolic-Associated Steatotic Liver Disease (MASLD)

by
Ilaria Barchetta
1,
Michele Zampieri
1,
Flavia Agata Cimini
1,
Sara Dule
1,
Federica Sentinelli
2,
Giulia Passarella
1,
Alessandro Oldani
1,
Katsiaryna Karpach
1,
Maria Giulia Bacalini
3,
Marco Giorgio Baroni
2,4,
Anna Reale
1 and
Maria Gisella Cavallo
1,*
1
Department of Experimental Medicine, Sapienza University of Rome, 00161 Rome, Italy
2
Endocrinology and Diabetes, Department of Clinical Medicine, Public Health, Life and Environmental Sciences (MeSVA), University of L’Aquila, 67100 L’Aquila, Italy
3
IRCCS Istituto delle Scienze Neurologiche di Bologna, 40139 Bologna, Italy
4
Neuroendocrinology and Metabolic Diseases, IRCCS Neuromed, 86077 Pozzilli, Italy
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2025, 26(3), 1271; https://doi.org/10.3390/ijms26031271
Submission received: 23 December 2024 / Revised: 30 January 2025 / Accepted: 31 January 2025 / Published: 31 January 2025
(This article belongs to the Section Molecular Endocrinology and Metabolism)
Review Reports Versions Notes

Abstract

Metabolic-associated steatotic liver disease (MASLD) represents the most common chronic hepatopathy worldwide and an independent risk factor for cardiovascular disease and mortality, particularly when liver fibrosis occurs. Epigenetic alterations, such as DNA methylation, may influence MASLD susceptibility and progression; yet mechanisms underlying this process are limited. This study aimed to investigate whether active DNA demethylation in peripheral blood mononuclear cells (PBMCs) from individuals with MASLD, alongside the methylation and mRNA levels of inflammation- and fibrosis-related candidate genes, is associated with liver fibrosis. For this study, global demethylation intermediates (5-hydroxymethylcytosine [5hmC], 5-formylcytosine [5fC]) were quantified in PBMCs from 89 individuals with/without MASLD using ELISA. Site-specific DNA methylation of SOCS3, SREBF1, and TXNIP was analyzed by mass spectrometry-based bisulfite sequencing; mRNA expression was assessed via RT-PCR. Individuals with MASLD and moderate-to-high fibrosis risk (estimated by the fibrosis non-alcoholic steatohepatitis (NASH) index, FNI) progressively exhibited greater global 5hmC and 5fC levels. Higher FNI was associated with reduced methylation of the SOCS3 gene and increased mRNA expression of the SOCS3, TXNIP, IL-6, and MCP-1 genes. In conclusion, elevated fibrosis risk in MASLD is associated with active global DNA demethylation, as well as differential methylation and expression patterns of genes, which are key regulators of inflammation and fibrosis. These epigenetic alterations in PBMCs may mirror DNA methylation changes in the liver, which may potentially contribute to liver fibrogenesis and represent novel biomarkers for MASLD progression toward fibrosis.
Keywords: epigenetics; DNA methylation; DNA demethylation; non-alcoholic fatty liver disease; metabolic-associated fatty liver disease; NASH; liver fibrosis; fibrosis NASH index; FNI epigenetics; DNA methylation; DNA demethylation; non-alcoholic fatty liver disease; metabolic-associated fatty liver disease; NASH; liver fibrosis; fibrosis NASH index; FNI

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MDPI and ACS Style

Barchetta, I.; Zampieri, M.; Cimini, F.A.; Dule, S.; Sentinelli, F.; Passarella, G.; Oldani, A.; Karpach, K.; Bacalini, M.G.; Baroni, M.G.; et al. Association Between Active DNA Demethylation and Liver Fibrosis in Individuals with Metabolic-Associated Steatotic Liver Disease (MASLD). Int. J. Mol. Sci. 2025, 26, 1271. https://doi.org/10.3390/ijms26031271

AMA Style

Barchetta I, Zampieri M, Cimini FA, Dule S, Sentinelli F, Passarella G, Oldani A, Karpach K, Bacalini MG, Baroni MG, et al. Association Between Active DNA Demethylation and Liver Fibrosis in Individuals with Metabolic-Associated Steatotic Liver Disease (MASLD). International Journal of Molecular Sciences. 2025; 26(3):1271. https://doi.org/10.3390/ijms26031271

Chicago/Turabian Style

Barchetta, Ilaria, Michele Zampieri, Flavia Agata Cimini, Sara Dule, Federica Sentinelli, Giulia Passarella, Alessandro Oldani, Katsiaryna Karpach, Maria Giulia Bacalini, Marco Giorgio Baroni, and et al. 2025. "Association Between Active DNA Demethylation and Liver Fibrosis in Individuals with Metabolic-Associated Steatotic Liver Disease (MASLD)" International Journal of Molecular Sciences 26, no. 3: 1271. https://doi.org/10.3390/ijms26031271

APA Style

Barchetta, I., Zampieri, M., Cimini, F. A., Dule, S., Sentinelli, F., Passarella, G., Oldani, A., Karpach, K., Bacalini, M. G., Baroni, M. G., Reale, A., & Cavallo, M. G. (2025). Association Between Active DNA Demethylation and Liver Fibrosis in Individuals with Metabolic-Associated Steatotic Liver Disease (MASLD). International Journal of Molecular Sciences, 26(3), 1271. https://doi.org/10.3390/ijms26031271

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