Metabolic dysfunction-associated Steatotic Liver Disease (MASLD) has emerged as a pressing global health challenge, affecting a nearly 30% of adults worldwide and with limited therapeutic options. Its progressive form, metabolic dysfunction-associated steatohepatitis (MASH), is particularly concerning due to its association with severe comorbidities including hepatocellular carcinoma, cardiovascular disease, and type 2 diabetes. The Metabo3DC project focuses on identifying the immunological mechanisms linking metabolic disturbances to disease progression to MASH. This project addresses this critical knowledge gap by focusing on conventional dendritic cells (cDC), which coordinate innate and adaptive immune responses, and whose role in MASH pathogenesis is underexplored. The core objective is to dissect the impact of the hepatic immune-metabolic environment impacts the transiting cDC during MASLD development and resolution. We aim to achieve this first by profiling these cells across the spectrum of MASLD severity and post MASLD resolution, with the goal of identifying disease-associated cDC subtypes, understanding their metabolic regulation, and testing how targeted metabolic interventions can alter disease outcomes. We will then use the markers identified to study how specific cDC phenotypes relate to hepatocyte damage and specific metabolic environments in the liver. By investigating the interplay between local liver metabolism and immune cell function, this project has the potential to redefine our understanding of MASH and open new avenues for targeted immunometabolic therapies. The multidisciplinary approach, integrating immunology, metabolism, and liver pathology, positions this work to make a significant impact on both the scientific understanding of chronic liver disease and the development of novel therapeutic strategies.
