FOR 5889:  How Death and Danger Signals dynamically control Stage Transitions in Chronic Hepatic Disease (dangerhep)

• Subject Area: Medicine
• Term: since 2026
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 546585894

Chronic liver diseases of various etiologies are inherently at risk of progressing through certain initially reversible stages of chronic inflammation to an irreversible stage of disease, hepatocellular carcinoma (HCC). A better understanding of the molecular mechanisms driving these stage transitions could lead to new approaches to more accurately predict the risk of developing HCC in individual patients and to develop novel, personalized strategies for cancer prevention. However, the exact relationship between liver injury and cell death, the immunological responses to this and the progression of liver disease is not well understood. Building on collaborative preliminary work, dangerhep aims to test the hypothesis that so-called danger signals such as “danger- or damage-associated molecular patterns” (DAMPs) play a key role in controlling stage transitions in chronic liver diseases. In nine interlinked projects and one platform project, we will investigate (i) which molecular mechanisms regulate the release of specific danger signals during liver injury, (ii) how these alarm signals control the dynamic interaction between hepatocytes and different subtypes of immune cells, and (iii) how these interactions mediate stage transitions in chronic liver diseases. These questions will be systematically addressed by an interdisciplinary team of experts in hepatology, cell biology, immunology, and innovative imaging techniques. A key element of dangerhep is 2-photon microscopy-based imaging in liver and adipose tissue, which allows real-time analysis of cell-cell interactions with unprecedented spatial and temporal resolution in vivo. This technology is complemented by specific expertise that each project leader brings to a common “methods toolbox”. The overarching goal is the structured translation of the mechanistic insights of dangerhep to the patient. In doing so, we aim to identify a new generation of non-invasive diagnostics and biomarkers, as well as novel targets for personalized HCC prevention in chronic liver disease. At the same time, as a consortium, we aim to contribute to the development of techniques and concepts that transcend current conceptional, interdisciplinary and methodological boundaries.

• DFG Programme: Research Units

Projects

• Coordination Funds (Applicant Lüdde, Ph.D., Tom )
• Defining the autophagy-mediated secretome and its impact during stage transitions in chronic liver disease (Applicant Kondylis, Ph.D., Evangelos )
• Exploring the function of apoptotic effector Caspases in stage transitions of hepatic diseases (Applicant Schneider, Anne Theres )
• Functional dissection of canonical vs. non-canonical NF-κB-dependent danger signals in hepatocellular carcinoma development (Applicant Vucur, Mihael )
• Functional intravital imaging platform (Applicant Ghallab, Ahmed )
• How danger signals control an immunological „point-of-no-return“ in the MASLD-HCC transition (Applicant Heikenwälder, Mathias )
• How release- and effector-mechanisms of DAMPs in sublethal hepatocyte necroptosis control transition points in hepatocarcinogenesis (Applicant Lüdde, Ph.D., Tom )
• Linear ubiquitination in the adipose tissue influences stage transitions in hepatic disease (Applicant Peltzer, Ph.D., Nieves )
• Lipogranuloma formation in steatohepatitis (Applicants Cadenas, Cristina ;  Hengstler, Jan G. )
• Role of stress response kinases in regulating cell death and subsequent release and action of DAMPs in the pathogenesis of MASH (Applicants Angendohr, Carolin ;  Bode, Johannes Georg )
• The role of sphingolipids as DAMPs in stage transitions from MASLD to HCC (Applicant Levkau, Bodo )

• Spokesperson: Professor Dr. Tom Lüdde, Ph.D.