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American Enterprise Institute

In the initiation stage of ferroptosis, long-chain fatty acid CoA ligase 4 (ACSL4) catalyzes the binding of PUFAs (such as arachidonic acid AA and adrenic acid AdA) to CoA via thioester bonds to form activated fatty acyl-CoA derivatives ( + ) to catalytically active Fe + through the NADPH-dependent electron transport system, continuously driving the Fenton reaction and accelerating the generation of hydroxyl radicals (OH), thus forming a self-reinforcing cycle of lipid peroxidation and ROS production ( 2.3 Dual defense network of the antioxidant system Cells have constructed a dynamic protective system against ferroptosis, which consists of an enzymatic defense system with the glutathione (GSH)-glutathione peroxidase 4 (GPX4) axis as the core and a multi-layered antioxidant network independent of GPX4

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KMT2B-dependent RFK transcription activates the TNF-alpha/NOX2 pathway and enhances ferroptosis caused by myocardial ischemia-reperfusion