Iron Overload, Oxidative Stress, and Ferroptosis in the Failing Heart and Liver

Abstract

Iron accumulation is a key mediator of several cytotoxic mechanisms leading to the impairment of redox homeostasis and cellular death. Iron overload is often associated with haematological diseases which require regular blood transfusion/phlebotomy, and it represents a common complication in thalassaemic patients. Major damages predominantly occur in the liver and the heart, leading to a specific form of cell death recently named ferroptosis. Different from apoptosis, necrosis, and autophagy, ferroptosis is strictly dependent on iron and reactive oxygen species, with a dysregulation of mitochondrial structure/function. Susceptibility to ferroptosis is dependent on intracellular antioxidant capacity and varies according to the different cell types. Chemotherapy-induced cardiotoxicity has been proven to be mediated predominantly by iron accumulation and ferroptosis, whereas there is evidence about the role of ferritin in protecting cardiomyocytes from ferroptosis and consequent heart failure. Another paradigmatic organ for transfusion-associated complication due to iron overload is the liver, in which the role of ferroptosis is yet to be elucidated. Some studies report a role of ferroptosis in the initiation of hepatic inflammation processes while others provide evidence about an involvement in several pathologies including immune-related hepatitis and acute liver failure. In this manuscript, we aim to review the literature to address putative common features between the response to ferroptosis in the heart and liver. A better comprehension of (dys)similarities is pivotal for the development of future therapeutic strategies that can be designed to specifically target this type of cell death in an attempt to minimize iron-overload effects in specific organs.

Genetic Characterization of Rat Hepatic Stellate Cell Line HSC-T6 for In Vitro Cell Line Authentication

“…Somewhat surprising is the finding that HSC-T6 express extremely high levels of the ferritin-heavy chain 1 ( Fth1 ). This protein has a ferroxidase activity, is involved in intracellular iron storage, and protects from ferroptosis [ 46 ]. In this regard, a previous report performed in smooth muscle cells demonstrated that increased ferritin heavy chain expression correlates with an enhanced differentiated phenotype [ 47 ].…”

Therapeutic Targets for DOX-Induced Cardiomyopathy: Role of Apoptosis vs. Ferroptosis

“…Several studies have recently demonstrated that DOX-induced cardiotoxicity is caused by ferroptosis, a novel form of cell death [99][100][101][102][103][104][105]. Ferroptosis is a type of programmed cell death dependent on iron, and is characterized by the accumulation of lipid peroxides.…”

Clinical and Molecular Aspects of Iron Metabolism in Failing Myocytes

“…The key regulators of ferroptosis seem to be glutathione peroxidase 4, ferroptosis suppressor protein 1, and oxidized cysteine (cystine)/glutamate antitransporter, known as Xc-system, inhibition of which induces ferroptosis. Ferroptosis has been proposed to play an important role in the occurrence and development of many diseases, including cancer, neurodegenerative disorders, ischemia/reperfusion injury, hematological malignancies, and cardiovascular diseases [ 65 , 77 , 78 ].…”