Prevalence of metabolic-dysfunction associated liver disease (MASLD) is growing due to the global overnutrition crisis promoting obesity and type 2 diabetes. This condition involves metabolic dysfunction leading to triglyceride buildup, inflammation, and fibrosis within the liver, contributing to significant morbidity and mortality. MASLD is a complex, heterogeneous, multisystemic and dynamic disease without approved therapy in Europe. Treatment challenges include the reliance on liver biopsies for diagnosis and the general “one-size-fits-all” drug development approach, which has demonstrated high failure rates. At present, lifestyle changes remain the cornerstone for MASLD primary management. Patient subtypes based on factors like age, sex, genetics, exposome and metabolomic profiles suggest that personalized and complementary approaches to identify distinct phenotypes might improve outcomes. MASLD progression involves interorgan communication, especially across the gut-liver-brain axis, that exhibit dynamic adaptive responses mediating disease progression and regression. The hepatic microcirculatory system, gut barrier, ammonia homeostasis and oxidative stress are key mechanisms for the disruption of cell homeostasis and host immunometabolism leading to fibrosis, immune dysfunction and cancer. The UNMASK project seeks to enhance understanding of MASLD by exploring its hierarchical mechanisms. A primary goal is to develop a portfolio of non-invasive biomarkers to improve MASLD diagnosis and patient classification and stratification. This program incorporates in vitro, in vivo, and clinical studies, aiming to replace invasive biopsies with real-world diagnostic applications. UNMASK’s legacy will include the creation of a non-invasive diagnostic tool for MASLD, improving patient care through more accurate, individualized approaches.