Project Details
Projekt
How release- and effector-mechanisms of DAMPs in sublethal hepatocyte necroptosis control transition points in hepatocarcinogenesis
Applicant
Professor Dr. Tom Lüdde, Ph.D.
Subject Area
Gastroenterology
Term
since 2026
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 546585894
Chronic liver diseases are characterized by a dynamic interplay between hepatocyte death, immune activation, and compensatory regeneration, ultimately promoting fibrosis and hepatocellular carcinoma (HCC). Among the different forms of programmed cell death (PCD), necroptosis has emerged as a central but incompletely understood driver of inflammation and cancer development. While necroptosis was traditionally considered a terminal event, our recent work using 2-photon microscopy has uncovered a previously unrecognized sublethal form of necroptosis in hepatocytes, associated with membrane leakiness and the release of specific danger-associated molecular patterns (DAMPs). This “hyper-necroptotic” state induces distinct immune responses and promotes hepatocarcinogenesis, as demonstrated in a novel genetic mouse model. Project P01 builds on these findings and aims to dissect the molecular basis and functional consequences of sublethal necroptosis on stage transitions in chronic liver disease. We hypothesize that sublethal necroptosis triggers a distinct DAMP signature that orchestrates the recruitment of specific immune cell subsets and promotes liver cancer development. Our central goal is to systematically define these mechanisms across four levels: (i) dissecting DAMP release dynamics in vitro using cell systems and primary hepatocytes; (ii) identifying immune effector mechanisms and validating DAMP functions in vivo in genetically engineered mouse models and a MASLD-HCC sequence; (iii) investigating the role of Ninjurin-1, a membrane rupture mediator, in modulating DAMP release and inflammation; and (iv) translating our findings into patient cohorts by correlating DAMP signatures with clinical progression in chronic liver disease and HCC. Project P01 is centrally embedded within the dangerhep consortium on both a conceptual and methodological level. As such, close conceptual synergies exist with P02-P04 (comparative analyses with apoptosis, lethal necroptosis, and secretory autophagy), P05-P07 (transfer of findings into the context of metabolic liver disease), and P08-P09 (specific effects of sublethal necroptosis on immune cell subsets). It also depends on and contributes to the consortium’s methods toolbox as a central element of synergy, including intravital 2-photon microscopy (C01), proteomics and lipidomics (P05, P07), the application of human precision-cut liver slices (P03), and human biobanking (P08). By integrating the project into the dangerhep consortium and thereby benefiting from our conceptual and methodological synergies, P01 aims to significantly advance our understanding of how regulated necrosis drives stage transitions of chronic liver diseases toward HCC, thereby laying the foundation for novel diagnostic and chemopreventive strategies in patients with chronic liver disease.
DFG Programme
Research Units
