Ferroptosis: A Trigger of Proinflammatory State Progression to Immunogenicity in Necroinflammatory Disease

Abstract

Until recently, necrosis is generally regarded as traumatic cell death due to mechanical shear stress or other physicochemical factors, while apoptosis is commonly thought to be programmed cell death, which is silent to immunological response. Actually, multiple modalities of cell death are programmed to maintain systematic immunity. Programmed necrosis, such as necrosis, pyroptosis, and ferroptosis, are inherently more immunogenic than apoptosis. Programmed necrosis leads to the release of inflammatory cytokines, defined as danger-associated molecular patterns (DAMPs), resulting in a necroinflammatory response, which can drive the proinflammatory state under certain biological circumstances. Ferroptosis as a newly discovered non-apoptotic form of cell death, is characterized by excessive lipid peroxidation and overload iron, which occurs in cancer, neurodegeneration, immune and inflammatory diseases, as well as ischemia/reperfusion (I/R) injury. It is triggered by a surplus of reactive oxygen species (ROS) induced in an imbalanced redox reaction due to the decrease in glutathione synthesis and inaction of enzyme glutathione peroxidase 4 (GPX4). Ferroptosis is considered as a potential therapeutic and molecular target for the treatment of necroinflammatory disease, and further investigation into the underlying pathophysiological characteristics and molecular mechanisms implicated may lay the foundations for an interventional therapeutic strategy. This review aims to demonstrate the key roles of ferroptosis in the development of necroinflammatory diseases, the major regulatory mechanisms involved, and its potential as a therapeutic target.

Exploring the Association between Glutathione Metabolism and Ferroptosis in Osteoblasts with Disuse Osteoporosis and the Key Genes Connecting them

“…The general process of ferroptosis can be decided two steps: (1) transferrin receptor 1 transports circulating iron to cells inside and (2) divalent iron ions are released to iron pool belonging to lysosomes [ 10 ]. The remote cause of this mechanism is usually due to the decline of glutathione synthesis and metabolism-related functions in cells, resulting in the excess of reactive oxygen species [ 11 ]. Many genes such as TFRC, P53, and GPX4 have been proved to be involved in the occurrence and development of ferroptosis [ 12 – 15 ].…”

Inhibition of lncRNA NEAT1 protects endothelial cells against hypoxia/reoxygenation‑induced NLRP3 inflammasome activation by targeting the miR‑204/BRCC3 axis

“…Although the data in the present study validated the key role and novel mechanism of the NEAT1/miR-204/BRCC3 axis in the regulation of NLRP3 inflammasome activation dependent-pyroptosis in vitro , the absence of in vivo animal experiments or human tissue samples reduces the clinical application potential of the conclusions. In addition, some other important forms of regulatory cell death, including ferroptosis, apoptosis, autophagy and necroptosis, have also been indicated to serve an important role in myocardial I/R injury ( 22 – 26 ). However, the present study did not focus on the effects of NEAT1/miR-204/BRCC3 signals on these forms of regulatory cell death.…”

The key roles of organelles and ferroptosis in Alzheimerʼs disease

“…Apoptosis is the main type of programmed cell death associated with homeostasis, which is characterized by internucleosomal DNA fragmentation, activation of caspases, decreased mitochondrial membrane potential, plasma membrane blistering, cell shrinkage, and nuclear fragmentation (Kerr et al, 1972; Li et al, 2021; Wang & Kanneganti, 2021). Necroptosis is considered a type of programmed cell death in the setting of physicochemical stimulation, including infection and oxidation.…”