Metabolic dysfunction-associated steatotic liver disease: Translating mechanisms to therapies

Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common chronic liver disease worldwide, affecting a staggering 30% of the general population. MASLD is the hepatic manifestation of metabolic syndrome, and its prevalence is expected to increase with an aging and more obese population. MASLD is a major contributor to life-threatening complications such as liver cirrhosis and hepatocellular carcinoma, with hepatic fibrosis being the key determinant of disease progression. While interventions targeting underlying metabolic risk factors like obesity and insulin resistance, primarily through weight loss, have shown some effectiveness, weight-lowering drugs such as semaglutide offer limited benefit for liver fibrosis. Liver-targeted pharmacotherapies have largely failed to yield promising results. Despite several phase 3 clinical trials in patients with metabolic dysfunction associated steatohepatitis (MASH), only resmetirom has recently obtained accelerated approval in the US, with a placebo-adjusted improvement in fibrosis of ~12% after 1 year of therapy. This challenging landscape and the paucity of liver-directed therapies constitutes a main motivation for founding a Transregio-CRC (CRC/TR) on MASLD, focusing on understanding, preventing and treating MASLD before the development of end-stage complications such as decompensated liver cirrhosis or hepatocellular carcinoma.

Aim

The overarching aim is to gain a holistic understanding of the disease-defining, liver-specific molecular and cellular events in MASLD. Two interrelated and synergistic research areas aim to understand heterogeneity in mechanisms of hepatocyte metabolic injury, subsequent inflammatory and fibrogenic responses as well as underlying cell-cell crosstalk in order to develop novel therapeutic concepts.       

Work plan

Projects in two interrelated research areas (A – metabolic injury, B – inflammation and fibrosis) will aim at understanding heterogeneity in mechanisms of hepatocyte metabolic injury, subsequent inflammatory and fibrogenic responses as well as the underlying cell-cell crosstalk in order to develop novel therapeutic concepts. Central projects will provide relevant cross-sectional technologies such as access to extensively phenotyped patient material, transcriptomics, bioinformatics, science data management and an integrated research training group. Together, we will define the events that govern the transition from benign steatosis to non-alcoholic steatohepatitis (NASH) and the involved key players; understand key drivers of hepatic inflammation and fibrogenesis in NAFLD; elucidate the cross-talk between different cell-types and metabolism – inflammation – fibrosis as well as interrelated feed-forward mechanisms in MASLD; and apply the above concepts to develop novel therapeutic approaches and concepts of multi-modal combination therapy in MASLD.  

The CRC/TR 412 MASLD in Berlin and Dresden will open prospects for a new generation of rationally designed and personalized treatment approaches that might prevent the liver of at risk individuals progress from metabolic risk to disease.