Gradual DNA methylation changes reveal transcription factors implicated in metabolic dysfunction-associated steatotic liver disease progression and epigenetic age acceleration

作者：Evelien Van Dijck, Steven Van Laere, Emilie Logie, Steven Timmermans, Erik Fransén, Joe Ibrahim, Timothy J. Kendall, Jonathan Fallowfield, Ligia Mateiu, Claude Libert, Guy Van Camp, An Verrijken, Luc Van Gaal, Sven Francque, Wim Van Hul, Wim Vanden Berghe · 发表于：Clinical Epigenetics · 年份：2025 · DOI：10.1186/s13148-025-01945-6 · 被引用次数：4 · 研究领域：Epigenetics and DNA Methylation、Ferroptosis and cancer prognosis、Genetic Associations and Epidemiology

BACKGROUND: Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common chronic liver disease worldwide, but its pathophysiological mechanisms remain elusive. It is a progressive disease, encompassing hepatic steatosis, steatohepatitis with (out) fibrosis, and ultimately cirrhosis and hepatocellular carcinoma. DNA methylation (DNAm) is dysregulated in MASLD and may play a central role in its pathogenesis. Additionally, aging is associated with MASLD and shares common processes of chronic inflammation and oxidative stress. Therefore, this study focuses on DNAm changes in relation to MASLD progression and epigenetic age acceleration (EAA). RESULTS: Liver biopsies from 22 individuals with varying MASLD status were analyzed using Infinium MethylationEPIC BeadChip arrays. Strikingly, progression of MASLD was characterized by gradual DNAm changes, revealing multiple associated KEGG pathways. Additionally, Horvath's EAA significantly correlated with MASLD stage and individual histological MASLD parameters while LiverClock's EAA correlated only with MASLD stage. In contrast, both Horvath's intrinsic EAA and HepClock's EAA showed no significant correlations. Integrative analyses, leveraging both gradual MASLD and Horvath's EAA DNAm signatures, gene expression (n = 118), and a MASLD-specific transcriptional regulatory network, identified (regulon-specific) transcription factors implicated in MASLD and EAA progression, representing a transcription factor-network ...