Figure 1.

Possible ferroptosis signaling pathway after cerebral ischemia

After cerebral ischemia, energy deficiency leads to impaired clearance of excitatory neurotransmitters in synaptic gaps, increasing the concentration of neurotransmitters such as glutamate, stimulating AMPA receptor activation, and mediating Na ⁺ influx. The increase in intracellular Na ⁺ leads to the conversion of prothrombin into active thrombin, thereby inducing the phosphorylation and activation of calcium-dependent cytosolic phospholipase A2α (cPLA2α). In addition, prothrombin in the blood may enter the brain through blood-brain barrier (BBB) disruption and be converted into thrombin, mediating cPLA2α activation by increasing cytoplasmic free Ca ²⁺. cPLA2α can cleave arachidonic acid (AA) at the sn-2 position of glycerophospholipids in the cell membrane. Subsequently, AA is converted to AA-CoA under catalysis of acyl-CoA synthetase long-chain family member 4 (ACSL4) and immediately incorporated into membrane phospholipids by lysophosphatidylcholine acyltransferase 3 (LPCAT3) to form AA-containing phospholipids (PL-AA). Under the catalysis of arachidonate 15-lipoxygenase (ALOX15) and Fenton reaction, PL-AA undergoes oxidation to produce biologically active lipid peroxides, which ultimately participate in ferroptosis. Glutathione peroxidase 4 (GPx4) can reduce lipid hydroperoxides (L-OOH) to lipid alcohols (L-OH). High concentrations of extracellular glutamate inhibit cysteine uptake, thereby limiting the biosynthesis of glutathione (GSH). GPx4 is inactivated due to a lack of necessary substrates, further leading to the accumulation of toxic lipid peroxides and ferroptosis. In addition, the decrease in soluble tau protein after cerebral ischemia inhibits the transport of amyloid precursor protein (APP) to the surface of neuronal membranes, blocking the interaction between APP and ferroportin (Fpn), and prevents the neuronal transfer of Fe ²⁺, leading to toxic intracellular accumulation of Fe ²⁺ and ultimately ferroptosis. (Created with BioRender.com). GCL: glutamate-cysteine ligase. GSS: glutathione synthetase. GSSG: Oxidized glutathione. GPCR: G protein-coupled receptor. ER: Endoplasmic reticulum.