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To Eat or Not to Eat-The Metabolic Flavor of Ferroptosis


To Eat or Not to Eat-The Metabolic Flavor of Ferroptosis

Minghui Gao et al. Curr Opin Cell Biol.


Ferroptosis is a newly defined iron-dependent, non-apoptotic mode of cell death with necrotic morphology. Distinctive from other death mechanisms, ferroptosis requires cellular iron and lipid peroxides, and is dictated by specific cellular metabolic processes. Importantly, ferroptosis has been implicated in a plethora of human diseases. This paper reviews the recent advances and outstanding questions of the field by focusing on the role of cellular metabolism in ferroptosis. The relevance of ferroptosis to disease and therapy is also discussed.


Figure 1
Figure 1. Regulation of ferroptosis by cellular metabolism
Ferroptosis is characterized by iron-dependent lipid peroxidation. Under normal conditions, glutathione synthesis axis, consisted of system Xc-/γ-GCS-GS/GPX4, counteracts lipid peroxidation and thus prevents ferroptosis. Ferroptosis inducers inhibit the system Xc-/γ-GCS-GS/GPX4 axis, leading to accumulation of lipid ROS (which is generated by the ACSL4/LPCTA3/LOX lipid peroxidation pathway). Transferrin receptor-mediated iron transportation and NCOA4-mediated ferritinophagy promote ferroptosis by sustaining cellular iron availability. Glutamine metabolic pathway, glutaminolysis, plays crucial roles in the death process. Glutaminolysis may contribute to lipid peroxidation by providing precursors towards fatty acid or lipid synthesis. Abbreviations: AA/AdA, arachidonic acid or adrenic acid; AA/AdA-CoAA, arachidonic acid or adrenic acid Coenzyme A; AA/AdA-PE, arachidonic acid or adrenic acid-phosphatidyl-ethanolamine; ACSL4, acyl-CoA synthetase long-chain family member 4; Cys, L-cysteine; γ-GC, gamma-glutamylcysteine; γ-GCS, γ- glutamylcysteine synthetase; GPX4, glutathione peroxidase 4; Gln, L-glutamine; GLS2, glutaminase 2; GS, Glutathione synthetase; GSH, reduced glutathione; GSSG, di-glutathione; Glu, L-glutamate; I/R Induced Organ Damage, ischemia/reperfusion induced organ damage; α-KG, α-ketoglutarate; LPCAT3, lysophosphatidylcholine acyltransferase 3; LOX, lipoxygenase; NCOA4, nuclear receptor coactivator 4; PE, phosphatidyl-ethanolamine; lipid ROS, lipid reactive oxygen species; TA, transaminases; TCA, tricarboxylic acid cycle; TFRC, transferrin receptor.

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