Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in western countries. It can be dichotomically divided into steatosis, associated with a benign outcome, and steatohepatitis (NASH), characterized by progression to fibrosis, hepatocellular carcinoma and increased mortality. It is estimated that 24% of European adults develop NAFLD, 10-30% of them will evolve to NASH, among which 10-15% develop fibrosis/cirrhosis. Currently, lifestyle adjustment remains the cornerstone of NAFLD management in the absence of any effective pharmacologic therapy, and the liver transplantation is the only option for NAFLD-related end-stage liver diseases. NAFLD is a complex and dynamic disease whose pathogenesis is poorly deciphered. Understanding of mechanisms involved in NAFLD development and progression is a key step for a better risk stratification. In parallel, pharmaceutical industries face bottleneck to develop new therapies because of the lack of human liver relevant models. Many animal models have been developed to reproduce NAFLD progress but they are not fully relevant due to their specific metabolisms. Simplistic 2D in vitro models are also limited when investigating NAFLD, which involves complex interactions between different cells and cells-extracellular matrix (liver is a complex organ with multicellular organization and most of cells are involved/affected during NAFLD). We hypothesize that the smart design of a complex multicellular NAFLD model will provide an unprecedented tool to investigate this disease. In this project, we plan to address 3 major goals to offer a relevant tool for the follow-up of NAFLD progression and treatment i) development of NAFLD-on-chip model from multicellular liver-on-chip mimicking in vivo liver architecture/physiology using human primary cells ii) identification of mechanisms and biomarkers involved in NAFLD progression and benchmark potential drugs iii) development of an integrated NAFLD mathematical model.