Relevance of ferroptosis and its therapeutic potential during acute liver injury and hepatocellular carcinoma formation

铁死亡的相关性及其在急性肝损伤和肝细胞癌形成过程中的治疗潜力

• 批准号: 461605562
• 负责人: Dr. Tobias Otto
• 金额: --
• 依托单位: Klinik für Gastroenterologie, Stoffwechselerkrankungen und Internistische Intensivmedizin (Med. Klinik III)
• 依托单位国家: 德国
• 项目类别: Priority Programmes
• 财政年份: 2021
• 资助国家: 德国
• 起止时间: 2020-12-31 至 2021-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/461605562?language=en
• 关键词: Relevance; ferroptosis; its; therapeutic; potential

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.

由于其在新陈代谢中的核心作用，肝脏会受到我们的饮食和摄入的其他物质的强烈影响。例如，毒素和药物不仅由肝脏代谢，而且有可能对肝脏造成严重损害。这种情况被称为急性肝损伤（ALI），在严重的情况下，它可以进展为肝功能衰竭，危及患者的生命。类似地，慢性肝病代表严重的临床问题。在许多西方国家，肥胖等基于营养的原因变得越来越明显。由于肥胖，观察到许多器官的变化。这种所谓的代谢综合征导致肝脏中脂肪沉积增强，这可能导致肝脏炎症（非酒精性脂肪性肝炎，NASH），慢性肝损伤，并最终形成肝细胞癌（HCC），最常见的肝癌形式。2018年，全球约有841，000例肝癌病例和782，000例肝癌死亡病例，肝癌是全球第三大癌症死亡原因。在包括HCC在内的急性和慢性肝病中，调节性细胞死亡是一种重要的细胞机制，可以根据细胞死亡发生的背景增强或减轻疾病的严重程度。最近，铁凋亡被发现是一种新的细胞死亡形式。其特征在于细胞膜中磷脂的铁依赖性过氧化，从而引发坏死样类型的细胞死亡。在本SPP的范围内，我们的目标是测试我们的工作假设，即铁凋亡有助于急性和慢性肝病的进展，因此是一个潜在的治疗靶点。也就是说，我们将专注于急性肝损伤（ALI）和肝细胞癌（HCC），并描述触发或逃避铁凋亡所需的细胞背景。该分析将主要涉及ALI和HCC形成的体内小鼠模型。这将通过细胞培养实验和人类HCC患者的数据进行补充。此外，我们的目的是阐明肝中的铁凋亡细胞死亡对免疫系统的影响，以及肝细胞发生铁凋亡和特异性免疫细胞功能改变之间的相互关系。我们还打算确定脂质过氧化产物，特别是发生在肝细胞和肝细胞癌细胞在铁凋亡细胞死亡。最后，我们计划将这些发现转化为新的治疗方案。在这方面，我们将调查的治疗价值，调节小鼠模型的急性肺损伤和肝细胞癌，使用药理学抑制剂和/或激活剂的铁凋亡。