Funding for Research
Chemical Biology of Ferroptosis in Health and Diseases
Ferroptosis is an iron-dependent cell death which was discovered recently. Ferroptosis is genetically, biochemically and morphologically distinct from other forms of cell death such apoptosis, necroptosis and autophagy. The ferroptotic cell death pathway is triggered by disregulation of iron metabolism, inhibition of glutathione (GSH) biosynthesis, inactivation of glutathione peroxidase 4 (GPX4), leading to lipid peroxidation. Recent studies have shown that ferroptosis is closely related to the pathophysiological processes of many diseases, such as cancer, cardiovascular diseases, stroke and neurodegeneration and diabetes (Figure 1). Our group is interested in understanding the role of ferroptosis in neurodegeneration and cardiovascular diseases and developing novel therapeutic strategies for the prevention of ferroptosis in various disease conditions.
Figure 1. Role of Ferroptosis in Various Human Diseases (Ref: Li J, Cao F, Yin HL, et al. Ferroptosis: past, present and future. Cell Death Dis. 2020;11(2):88).
Ferroptosis in Heme-Mediated Activation of Human Platelets
Our group has reported that ferroptosis plays a key role in the heme-mediated activation of human platelets. Hemolysis, a process by which the destruction of red blood cells leads to the release of hemoglobin, is a critical event observed during hemolytic disorders. Under oxidative stress conditions, hemoglobin can release its heme prosthetic group, which is highly cytotoxic and can catalyze the generation of reactive oxygen species (ROS), leading to several undesired redox reactions in the cells. We demonstrated for the first time that heme can mediate the activation and death of human platelets through ferroptosis. This study also suggested that the heme-mediated lipid peroxidation and ferroptosis in platelets may play an important role in hemolytic disorders.
Figure 2. Ferroptosis in human platelets (Ref: NaveenKumar SK, SharathBabu BN, Hemshekhar M, Kemparaju K, Girish KS, Mugesh G. The Role of Reactive Oxygen Species and Ferroptosis in Heme-Mediated Activation of Human Platelets. ACS Chem Biol. 2018;13(8):1996-2002).
Release of free heme during hemolysis upregulates heme oxygenase 1 (HO-1) enzyme, which catalyzes the release iron through heme degradation. The iron(II) released from heme mediates Fenton-type reaction to produce hydroxyl radicals and lipid peroxidation in platelets. We demonstrated that the classical ferroptosis inhibitors such as ferrostatin-1 can suppress ferroptosis by scavenging hydroxyl radicals.