Programme features

Dear colleagues and friends,

The liver plays a critical role in numerous physiological processes, including glucose and lipid metabolism, coagulation, iron homeostasis, bile secretion, and immune interactions. A disbalance in the synthesis, secretion, and uptake of lipids causes metabolic dysfunctionassociated steatotic (fatty) liver disease (MASLD), previously termed non-alcoholic fatty liver disease. MASLD is a worldwide epidemic that can lead to hepatic inflammation (MASH), fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). The disease is typically a hepatic manifestation of the metabolic syndrome that accompanies obesity and is often overlooked because the liver manifestations are clinically silent until late-stage disease is present (i.e., cirrhosis). The numbers are devastating: chronic liver diseases affect hundreds of millions of people globally with a significant impact on society. MASLD is considered the most frequent cause of chronic liver failure, with a prevalence of ~30% worldwide. Moreover, as MASLD is a major risk factor for the developing MASH, liver fibrosis, cirrhosis, hepatocellular carcinoma, cardiovascular diseases and type 2 diabetes, ~20% of these individuals have MASH and 20% of this group will develop cirrhosis over the next 3-4 decades. With the increasing numbers of obesity worldwide, these numbers are expected to significantly rise even further.

Given these dauting prospects, numerous pharmacological compounds that target the different molecular targets involved in the pathobiology of MASLD/MASH are currently in clinical testing, focusing on compounds with anti-metabolic, anti-inflammatory or anti-fibrotic properties. However, numerous study programs, even in late-phase trials, have been halted because of lack of efficacy, safety concerns or drug-drug interactions. It appears the drug development programs have turned into a drug development graveyard. Only Resmetirom has been very recently (2024) approved by the FDA as the first medication specifically developed to treat MASLD/MASH. Thus, the most prevalent management of MASLD/MASH to date is still dietary restriction and change of life style/weight-loss, if detected early enough.

Obviously, drug testing in healthy and diseased humans is largely restricted by ethical constraints, especially during early stages of drug development. One major hurdle in early stages of drug development is the fact that the liver metabolism is very different between humans and other animal species. To overcome these problems, in the last years we have witnessed a surge of various new and promising model systems, representing key aspects of liver function and sometimes even liver structure. This bears great promise for biochemical and cell biological elucidation of molecular and cellular pathways, ultimately allowing the identification of novel druggable key nodes in biochemical pathways.

For this advanced course, we will bring together experts and frontiers in five highly relevant and interconnected topics:

Liver (patho)physiology: In the last decades, liver metabolism has been extensively investigated. However, much is unclear. Is metabolic dysfunction about quantity or about genetic backgrounds such as PNPLA3? These studies also often ignore the involvement and regulation of metabolic zonation in the liver with relevance for e.g. (steroid) hormones, morphogens, gender differences and the circadian clock. Also, the remarkable regenerative capacity of the liver plays an as yet unknown role in liver metabolism.
Hepatocyte metabolism: In the end, lipid accumulation in hepatocytes causes and defines liver steatosis. However, much remains unclear. Hepatocytes are unique in that they can store neutral lipids in large lipid droplets (LDs), a feature typically observed only in professional storing cells such as adipocytes. The unusual lipid storage in large LDs results in macrovesicular steatosis that affects hepatocyte functioning. Current research focusses on hepatocyte lipid metabolic dysfunction related to mitochondrial function (fatty acid oxidation and oxidative stress leading to ferroptosis) as well as disbalance between neutral lipid storage in lipid droplets and secretion in lipoproteins.
Liver fibrosis: Although hepatocyte injury is a key driver of MASH, multiple other cell lineages within the hepatic fibrotic niche play major roles in the perpetuation of inflammation, mesenchymal cell activation, extracellular matrix accumulation as well as fibrosis resolution. The constituents of this cellular interactome, and how the various subpopulations within the fibrotic niche interact to drive fibrogenesis is an area of active research. Important cell types of the fibrotic niche include endothelial cells, macrophages, immune cells and myofibroblasts such as hepatic stellate cells.
Hepatocellular carcinoma (HCC): It is currently unknown how liver steatosis is a major risk factor in the development of HCC. Cancer cells accumulate many genetic alterations throughout their lifetime, but only so-called driver mutations drive cancer progression. Driver mutations may vary between cancer types and patients, can remain latent for a long time and become drivers at particular cancer stages, suggesting that other factors, e.g. environmental factors such as diet, may drive oncogenesis. The high mutational, biochemical, and histological tumor heterogeneity makes driver mutation identification very challenging.
Novel model systems: Preclinical MASLD/MASH models need to be adapted to recapitulate human conditions to select the best therapeutic candidates for clinical development and aid the delivery of personalized medicine. Currently, there is a surge of three-dimensional liver models based on spheroids, organoids, organ-an-a chip, 3D bioprinting, humanized mouse livers, and precision cut liver slices. These models can also be applied to the study of HCC, recapitulating the tumour microenvironment with mutated hepatocytes and cancer-associated fibroblasts.

In this advanced course the five topics will be discussed in depth by experts in the field. On a daily basis, there will be special emphasis on novel technologies that provide novel breakthroughs in the field (technology lectures) and that are therefore of interest for a new generation of scientists (graduate students and postdocs). In the special evening lectures, novel model systems with a clear connection towards the topic of that day will be explored in greater detail. The course will be organized in an informal setting to facilitate contacts and information exchange. Poster sessions, oral presentations, round table discussions and informal meet-the-expert sessions are scheduled to stimulate interactions between the participants and the lecturers/tutors.

The FEBS Advanced Lecture Course ‘MASLD: from novel liver model systems to organelle pathophysiology’ will take place on the island of Spetses, Greece, 3 to 8 September 2026. 

It is organised by :

Bernd Helms, Benedetta Artegiani, Delilah Hendriks, and Panu K. Luukkonen