Project Details
Projekt
How danger signals control an immunological „point-of-no-return“ in the MASLD-HCC transition
Applicant
Professor Dr. Mathias Heikenwälder
Subject Area
Gastroenterology
Term
since 2026
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 546585894
The consequence of chronic inflammatory diseases is the death of hepatocytes, immune activation and regeneration, which promote the development of hepatocellular carcinoma (HCC). The obesity epidemic has caused many metabolic diseases, including metabolic dysfunction-associated steatotic liver disease (MASLD). MASLD is a chronic liver disease characterized by abnormal fat accumulation and associated organelle stress (e.g. from high-calorie diets without (MASH) or with chronic alcohol abuse (Met/ALD). Identify that alter the metabolic program of hepatocytes, promote specific dangerous molecular patterns (DAMPs), and thus cause MASLD and HCC release. We hypothesize that (1) accumulation of DAMPs leads to immunological reprogramming in the liver in MASLD. (2) These changes affect the development of liver cancer. (3) Several of these changes are reversible. However, there are irreversible changes, which we define as immunological and molecular "point of no return. Our aim is to identify these underlying reversible and non-reversible molecular and cellular changes in MASH, Met-ALD pathogenesis and transition to HCC. The project builds on this prior work and aims to clarify the spatiotemporal specific role of DAMPs, liver immune cells and metabolites in MASH/Met-ALD and HCC transition. This will be investigated within four work packages: (i) Spatiotemporal, invasive/non-invasive analysis of DAMPs, metabolites and immune cell populations over time in MASLD and MASLD-HCC. (ii) Defining the "point of no return" of MASLD-HCC transition in preclinical mouse models. (iii) Effects of resmetirom on the risk of developing MASLD-HCC. (iv). Confirmation of markers from preclinical MASLD liver cancer models in patients.P09 is closely embedded in the dangerhep consortium. Synergies exist with P01-P04 (metabolism, necroptosis), P05-P07 (metabolic analyzes and liver diseases) and P08 (effects on immune cell populations and disease progression). The project uses consortium platforms, including 2-photon imaging (C01), proteome and lipidome analyzes (P05, P07) as well as the biobank (P08) and provides expertise in high-resolution metabolic (SPACE-M), multiplex protein analyzes (CODEX; MACSIMA) and mouse models of chronic inflammation. P09 is intended to contribute significantly to an integrative understanding of the transition from fatty liver to liver cancer and possible strategies for patients fatty liver and high risk of liver cancer.
DFG Programme
Research Units
