Ferroptosis in neutrophils.

Abstract

Ferroptosis is a distinct form of regulated cell death characterized by iron-dependent lipid peroxidation. The ferroptosis mechanism involves complex interactions between fatty acid metabolism, iron metabolism, lipid peroxidation, and antioxidative defense mechanisms. Fatty acids, especially polyunsaturated fatty acids (PUFAs), are susceptible to peroxidation, leading to the formation of lipid peroxides. Iron metabolism plays a critical role, as excessive free iron catalyzes the production of reactive oxygen species (ROS) via the Fenton reaction, further promoting lipid peroxidation. Antioxidative mechanisms, including glutathione peroxidase 4 (GPX4) and other components of the glutathione system, are crucial for neutralizing lipid peroxides and preventing ferroptosis. Recent studies have highlighted the role of ferroptosis in neutrophils, particularly under pathological conditions. Neutrophils, due to their high iron content and abundance of PUFAs, are inherently predisposed to ferroptosis. Recent studies indicates that polymorphonuclear myeloid derived suppressor cells (PMN-MDSCs) and tumor-infiltrating neutrophils (TINs) exhibit high susceptibility to ferroptosis due to dysregulated antioxidant defense mechanism through hypoxia-mediated downregulation of GPX4. Conversely, TINs resist ferroptosis through nuclear factor erythroid 2-related factor 2 (Nrf2)-dependent antioxidant pathway. Moreover, neutrophils induce ferroptosis in various cell types, such as endothelial cells, smooth muscle cells, and cardiomyocytes, through the release of neutrophil extracellular traps (NETs). This NET-mediated ferroptosis contributes to the pathogenesis of conditions such as intestinal ischemia-reperfusion injury, aortic aneurysm, acute lung injury, and doxorubicin-induced cardiotoxicity. This review consolidates current knowledge on the mechanisms of ferroptosis in neutrophils and its implications in disease progression and immune regulation. Understanding these processes may provide new therapeutic targets for modulating immune responses and improving outcomes in ferroptosis-related diseases.