Epigenetic signatures and cellular stress response pathways in metabolic dysfunction-associated steatotic liver disease: a personalized medicine perspective

Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common chronic liver disease around the world, with at least 40% global prevalence. Although genetic susceptibility contributes to disease risk, it does not fully explain the marked interindividual variability in disease onset, severity, and progression. Increasing evidence indicates that epigenetic mechanisms act as critical mediators between genetic predisposition and environmental exposures, shaping hepatic stress responses and metabolic dysfunction in MASLD. Epigenetic regulation, including DNA methylation and histone modifications, plays a fundamental role in maintaining metabolic homeostasis and coordinating cellular responses to metabolic, oxidative, and organellar stress, e.g., endoplasmic reticulum stress. Dysregulation of these processes has been consistently associated with hepatic steatosis, inflammation, fibrosis, and disease progression. Moreover, epigenetic control of circadian rhythms and molecular clock pathways further link metabolic imbalance to liver dysfunction and biological aging. Importantly, epigenetic signatures are stable, positioning them as attractive biomarkers for disease diagnosis, prognosis, and patient stratification, but also potentially reversible, making them promising targets for therapeutic intervention. Advances in epigenomic profiling and translational research are increasingly supporting the integration of epigenetic information into personalized medicine approaches for MASLD. In this review, we synthesize current experimental and translational evidence on epigenetic alterations involved in MASLD pathophysiology, with a particular focus on their role in cellular stress response pathways. We discuss the potential of epigenetic signatures as biomarkers and therapeutic targets, highlighting their relevance for the development of precision-based strategies in the management of MASLD.