Project Details
Projekt
Relevance of ferroptosis and its therapeutic potential during acute liver injury and hepatocellular carcinoma formation
Applicant
Dr. Tobias Otto
Subject Area
Cell Biology
Term
from 2021 to 2022
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 461605562
Due to its central role in metabolism, the liver can be strongly affected by our diet and other substances ingested. For instance, toxins and drugs are not only metabolized by the liver but also have the potential to induce severe damage to the liver. This condition is called acute liver injury (ALI) and in severe cases, it can progress to liver failure, a life-threatening condition to the patient. Similarly, chronic liver diseases represent a serious clinical problem. In many Western countries, nutrition-based causes such as obesity are becoming more and more pronounced. As a consequence of obesity, changes in many organs are observed. This so-called metabolic syndrome causes enhanced fat deposition in the liver, which can lead to liver inflammation (non-alcoholic steatohepatitis, NASH), chronic liver injury, and eventually to formation of hepatocellular carcinoma (HCC), the most common form of liver cancer. In 2018, an estimated 841,000 cases of liver cancer and 782,000 deaths from liver cancer occurred worldwide, ranking liver cancer as third most common cause of death among cancer worldwide.During both acute and chronic liver diseases including HCC, regulated cell death is an important cellular mechanism that can enhance or reduce disease severity depending on the context in which this cell death occurs. Recently, ferroptosis has been discovered as a novel form of regulated cell death. It is characterized by iron-dependent peroxidation of phospholipids in the cellular membrane, thereby triggering a necrotic-like type of cell death. Within the scope of this SPP, we aim to test our working hypothesis that ferroptosis contributes to progression of acute and chronic liver diseases and thus is a potential therapeutic target. Namely we will concentrate on acute liver injury (ALI) and hepatocellular carcinoma (HCC), and characterize the cellular context that is required to trigger or evade ferroptosis. This analysis will primarily involve in vivo mouse models of ALI and HCC formation. This will be complemented by cell culture experiments and data from human HCC patients. Furthermore, we aim to elucidate the impact of ferroptotic cell death in the liver on the immune system and the reciprocal relationship between hepatocytes undergoing ferroptosis and functional alterations of specific immune cells. We also intend to identify lipid peroxidation products occurring specifically in hepatocytes and HCC cells during ferroptotic cell death. Finally, we plan to translate these findings into novel treatment options. In this regards, we will investigate the therapeutic value of modulating ferroptosis in mouse models of ALI and HCC using pharmacological inhibitors and/or activators of ferroptosis.
DFG Programme
Priority Programmes
