Ferroptosis:mechanisms and links with diseases

Ferroptosis is an iron-dependent cell death,which is different from apoptosis,necrosis,autophagy,and other forms of cell death.The process of feroptotic cell death is defined by the accumulation of lethal lipid species derived from the peroxidation of lipids,which can be prevented by iron chelators(e.g.deferiprone,deferoxamine)and small lipophilic antioxidants(e.g,ferrostatin,liproxstatin).This review summarizes current knowledge about the regulatory mechanism of ferroptosis and its association withseveral pathways,including iron,lipid,and cysteine metabolism.We have further discussed the contribution of ferroptosis to thepathogenesis of several diseases such as cancer,ischemia/reperfusion,and various neurodegenerative diseases(e.g.Alzheimersdisease and Parkinson's disease),and evaluated the therapeutic applications of ferroptosis inhibitors in clinics.

Ferroptosis promotes T-cell activation-induced neurodegeneration in multiple sclerosis

While many drugs are effective at reducing the relapse frequency of multiple sclerosis (MS), there is an unmet need for treatments that slow neurodegeneration resulting from secondary disease progression. The mechanism of neurodegeneration in MS has not yet been established. Here, we discovered a potential pathogenetic role of ferroptosis, an iron-dependent regulated cell death mechanism, in MS. We found that critical ferroptosis proteins (acyl-CoA synthetase long-chain family member 4, ACSL4) were altered in an existing genomic database of MS patients, and biochemical features of ferroptosis, including lipid reactive oxygen species (ROS) accumulation and mitochondrial shrinkage, were observed in the experimental autoimmune encephalitis (EAE) mouse model. Targeting ferroptosis with ferroptosis inhibitors or reducing ACSL4 expression improved the behavioral phenotypes of EAE mice, reduced neuroinflammation, and prevented neuronal death. We found that ferroptosis was an early event in EAE, which may promote T-cell activation through T-cell receptor (TCR) signaling in vitro and in vivo. These data indicate that ferroptosis may be a potential target for treating MS.

Thrombin induces ACSL4-dependent ferroptosis during cerebral ischemia/reperfusion

Ischemic stroke represents a significant danger to human beings,especially the elderly.Interventions are only available to remove the clot,and the mechanism of neuronal death during ischemic stroke is still in debate.Ferroptosis is increasingly appreciated as a mechanism of cell death after ischemia in various organs.