Non-alcoholic fatty liver disease (NAFLD) encompasses a continuous spectrum ranging from hepatic fat accumulation to inflammation, fibrosis and cirrhosis. Worldwide, 25% of the population suffers from these hepatic disorders. Although an uncontrolled non-alcoholic steatohepatitis can lead to severe health issues, currently no effective therapeutic strategies are available. The current project investigates the crosstalk and a novel discovered interaction between two transcription factors central in the control of energy metabolism, more specifically PPARα, which is the target of lipid profile-normalizing drugs, and ERRα, which is highly expressed in liver and involved in energy pathway control. Recently, both proteins were independently linked to NAFLD. Changes in levels/activities of both proteins and functional implications of their crosstalk will be monitored in the NAFLD context, both in human and murine samples. Therapeutic effects of combining PPARα and ERRα-targeting drugs will be evaluated at various stages in several murine models mimicking human NAFLD. In parallel, DNA-binding capacities and gene-profiling following an interaction between PPARα and ERRα will be characterized at the genome-wide level. Complementing biophysical studies will deliver molecular insights towards interaction-breaking tools. Collectively, the results will allow assessing whether and at what stage interaction-modulating approaches may be viable strategies against progressive forms of NAFLD.