Epigenetic regulation in MASLD - insight for therapeutic target discovery.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most prevalent chronic liver disease. It encompasses metabolic affections that arise primarily from lifestyle and diet, independent of alcohol consumption. Particularly, the global rise in obesity constitutes a major risk factor and comorbidity, contributing to the prevalence and severity of MASLD. Despite its widespread impact and potential progression to severe liver pathologies, effective therapies remain limited, underscoring the urgency to better understand its underlying molecular mechanisms.Epigenetic regulation is essential for maintaining hepatic metabolic function and cellular identity in response to metabolic cues but becomes critically dysregulated during MASLD. Alterations in DNA methylation, histone modifications, and non-coding RNAs contribute to disease progression, promoting metabolic dysfunction and lipid accumulation. Recent evidence indicates that epigenetic dysregulation in MASLD also occurs in a spatial manner where changes in chromatin accessibility, zone-enriched microRNAs, and transcription factor activity can disrupt gene expression along the periportal-pericentral axis, leading to zone-specific disturbances in metabolic specialization, which emerges as a critical novel factor influencing the onset and progression of MASLD. Furthermore, this review explores the role of microRNAs and extracellular vesicles in mediating systemic metabolic dysfunction observed in MASLD and highlights emerging epigenetic strategies with therapeutic potential in MASLD.