Project Details
Projekt
The role of sphingolipids as DAMPs in stage transitions from MASLD to HCC
Applicant
Professor Dr. Bodo Levkau
Subject Area
Gastroenterology
Term
since 2026
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 546585894
Dysregulated metabolism of hepatic sphingolipids (SLs) is both a hallmark and a driver of metabolic dysfunction-associated steatotic liver disease (MASLD) and its progression to hepatocellular carcinoma (HCC). Evidence from genetic and pharmacological studies suggested that alterations in key enzymes of sphingolipid metabolism causally contribute to the pathogenesis of MASLD and HCC. However, the specific SL species acting as danger- or damage-associated molecular patterns (DAMPs) and their mechanistic roles remain unidentified and poorly understood. This project aims to identify and functionally characterize specific SL signatures as DAMPs in the transition from MASLD to HCC and to explore their causal relationships to cell death, metabolism, immunity, and inflammation. Our preliminary data show that mice deficient in sphingosine kinase 2 (SK2), which consequently exhibit altered levels of sphingosine-1-phosphate (S1P), the final product of SL synthesis and a potent bioactive lipid with immuno- and apoptosis-modulatory properties, demonstrate resistance to MASLD and HCC. In contrast, pharmacological inhibition of the first and rate-limiting step of SL synthesis, catalyzed by serine palmitoyltransferase (SPT), induces cholestasis and hepatocyte death. Genetic ablation of SPT promotes tumorigenesis, although the underlying mechanisms remain unclear. In P07, we will map the sphingolipidome in a disease stage-specific manner (from MASLD to HCC) using targeted and untargeted sphingolipidomics via liquid chromatography-tandem mass spectrometry (LC-MS/MS) and quadrupole time-of-flight (QTOF) mass spectrometry to define stage-specific SL-based DAMP signatures. We will then utilize primary hepatocytes, genetically modified mouse models, and pharmacological approaches in collaboration with multiple dangerhep groups to identify the causally involved SL-DAMPs and investigate their modes of action by studying their generation, degradation, transport, signaling, and cellular effects. Through our lipidomics expertise, P07 will provide cross-cutting analysis of SL-associated DAMPs for all dangerhep projects, while reverse input from individual dangerhep partners will enable functional linkage of SL-DAMP signatures to broader disease mechanisms. The ultimate goal of P07 is to translate refined SL-DAMP signatures to human MASLD/HCC cohorts, establish SL-based risk scores for disease assessment and prognosis, and identify novel targets within SL metabolism that may serve as the basis for chemopreventive and therapeutic interventions in the transition from MASLD to HCC.
DFG Programme
Research Units
