The role of RIPK1-dependent signaling cues in chronic liver disease and HCC

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Cell death represents a basic biological paradigm that governs outcomes and long-term sequelae in almost every liver disease. While in the normal liver, almost all cells are in a dormant G0 phase with little turnover, this condition is disturbed in chronic liver disease, where viral, toxic, metabolic or autoimmune injuries result in hepatocellular death, followed by inflammation and compensatory hepatocyte proliferation. Although these responses ensure efficient regeneration in the setting of acute hepatocellular injury, chronic hepatocyte death and the associated inflammation have been closely linked to the development of fibrosis, cirrhosis and hepatocellular carcinoma (HCC). Accordingly, HCC almost exclusively develops in patients with chronic liver disease (CLD), with cell death being the fundamental driver of this sequence leading towards cancer. The findings generated within the previous funding period of my DFG grant implicated that the cell death regulator RIPK1 plays a fundamental role in the regulation of programmed cell death, compensatory regeneration, hepatic inflammation and carcinogenesis in the liver. Moreover, our data suggested that a posttranslational modification of RIPK1 might be crucial for its role as signaling nodule in hepatocarcinogenesis. In this follow up grant proposal, we will build up on the successful previous funding period, groundbreaking preliminary unpublished findings and new experimental tools that we developed and which are ready to use for this proposal to functionally characterize pathways that might modulate the activation and function of RIPK1 in hepatocarcinogenesis. We also will systematically analyze how these newly characterized pathways influence liver cancer formation in human patients with chronic liver disease. The specific objectives of this research proposal are:- Assessing the role of TBK1/IKKepsilon in hepatocyte programmed cell death and cell death responses- Investigating the functional effects of TBK1/IKKepsilon and their interactions with TAK1 and RIPK1 in liver injury and HCC development- Defining the cell-type-specific functions of Gasdermin D and Gasdermin E in hepatocytes- Investigating the specific functions of Gasdermin D and Gasdermin E in TAK1/RIPK1-dependent liver cancer development- Assessing the prognostic relevance of the TBK1/IKKepsilon- and Gasdermin D/E-related signaling modules in human HCCUpon successful completion of these work-packages, we expect to establish a new and comprehensive view on the role played by RIPK1-dependent signaling cues in hepatocarcinogenesis. We also expect to identify novel promising candidates for pharmacological targeting which could be used for risk prediction as well as chemo-preventive strategies against HCC in patients with chronic liver disease.