Ferroptosis in Hepatocellular Carcinoma: Mechanisms, Drug Targets and Approaches to Clinical Translation

SIMPLE SUMMARY: In recent decades, scientific discoveries brought up several new treatments and improvements for patients suffering from hepatocellular carcinoma (HCC). However, increasing resistance to current therapies, such as sorafenib, worsen the outcome of HCC patients, leading to a search for alternative therapeutic strategies. The term ferroptosis describes a novel form of regulated cell death, which is different from apoptosis and necroptosis in a mechanistical and morphological manner. The main mechanism, which leads to cell death, is lipid peroxidation, caused by iron overload and the accumulation of polyunsaturated fatty acids. Recent studies demonstrate that ferroptosis can hamper the carcinogenesis in several tumor entities and in HCC. Therefore, a better understanding and a deeper insight in the processes of ferroptosis in HCC and the possible application of it in the clinical practice are of extreme importance. ABSTRACT: Ferroptosis, an iron and reactive oxygen species (ROS)-dependent non-apoptotic type of regulated cell death, is characterized by a massive iron overload and peroxidation of polyunsaturated fatty acids (PUFAs), which finally results in cell death. Recent studies suggest that ferroptosis can influence carcinogenesis negatively and therefore may be used as a novel anti-cancer strategy. Hepatocellular carcinoma (HCC) is a deadly malignancy with poor chances of survival and is the second leading cause of cancer deaths worldwide. Diagnosis at an already late stage and general resistance to current therapies may be responsible for the dismal outcome. As the liver acts as a key factor in iron metabolism, ferroptosis is shown to play an important role in HCC carcinogenesis and, more importantly, may hold the potential to eradicate HCC. In this review, we summarize the current knowledge we have of the role of ferroptosis in HCC and the application of ferroptosis as a therapy option and provide an overview of the potential translation of ferroptosis in the clinical practice of HCC.