Epigenomic Cascades Across Organs in Metabolic Dysfunction-Associated Steatotic Liver Disease: New Therapeutic Horizons.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common chronic liver disorder worldwide, affecting approximately one-third of the population and increasing the risk of severe hepatic and cardiovascular complications. Growing evidence indicates that MASLD is a systemic disease in which epigenetic changes-including DNA and RNA methylation as well as histone modifications-drive its progression by integrating metabolic and inflammatory signals across organs. This review introduces the concept of "networked epigenome cascades" and highlights how epigenetic alterations in extrahepatic metabolic organs contribute to insulin resistance (IR) and systemic inflammation. MASLD is thereby reframed as a disorder of systemic epigenomic miscommunication rather than a liver-only disease. We further discuss preclinical and emerging interventions, with an emphasis on natural compounds that modulate epigenomic regulation, while noting the uncertainties that remain regarding their translational potential for MASLD. By positioning the epigenome as a central mechanism, this review underscores its promise for biomarker development and mechanistically targeted interventions, although robust validation in humans is still required.