Fig. 1

The main pathways related to ferroptosis in EBI after SAH. Extracellular Fe³⁺ mainly binds to TRF and enters cells through TFR1, forming endosomes. HSF1 can inhibit the activity of TFR1 and reduce Fe³⁺ influx by activating HSPB1. Fe³⁺ in the endosome is reduced to Fe²⁺ by STEAP3, and Fe²⁺ is transported to cells through DMT1. Intracellular free iron can be stored in ferritin or transported out of cells through FPN1. NCOA4 mediates ferrithinophage to increase intracellular free iron. Free Fe²⁺ mediates the Fenton reaction to produce reactive oxygen species. FPN1 can reduce intracellular iron concentration by transporting Fe²⁺ out of cells. Hepcidin can inhibit CP’s oxidation of Fe²⁺ to Fe³⁺, promote DMT1’s transport of Fe²⁺ into cells, and inhibit FPN1’s transport of Fe²⁺ out of cells, resulting in an increase in intracellular iron concentration. GSH/GPX4 and FSP1, as the main antioxidant systems, inhibit the production of reactive oxygen species by lipid peroxides. SIRT1 can promote the expression of FSP1 and GPX4, enhancing antioxidant capacity. AA/AdA is absorbed into cells through FAT/FATP, and under the catalysis of ACSL4, CoA, and AA (AdA) are linked to form coenzyme AA-CoA (AdA-CoA) intermediates, which are then catalyzed by LPCAT3 to form arachidonic acid phosphatidylethanolamide (PE-AA) (PE-AdA). PE-AA (PE-AdA) catalyzes the formation of PE-AA-OOH (PE-AdA-OOH) through LOX/ALOX15, producing reactive oxygen species to promote ferroptosis. MUFA can competitively inhibit the function of FAT/FATP. PEBP1 promotes the activity of LOX/ALOX15, increases reactive oxygen species, and promotes ferroptosis, while CEP inhibits LOX/ALOX15 activity. System Xc⁻ transfers cysteine into the cell and transfers an equal amount of glutamate out of the cell. Cysteine enters cells and is reduced to cysteine by consuming NADPH. Glutathione (GSH) is synthesized from glutamate, cysteine, and glycine under the catalysis of glutamate cysteine ligase (GCL) and glutathione synthase (GS). Glutathione, as an electron donor, reduces toxic phospholipid hydroperoxides to non-toxic phospholipid alcohols, thereby inhibiting lipid peroxidation. P53 exerts its effect by inhibiting the functions of SLC7A11 and GPX4. Nrf2 can promote ferritin binding to Fe²⁺, promote FPN1 to transport Fe²⁺ out of cells, and thus reduce intracellular iron. It can also activate downstream GSH and GPX4 to inhibit lipid peroxidation. ROS reactive oxygen species, TFR1 transferrin receptor 1, DMT1 divalent metal transporter 1, FPN ferroportin, CP ceruloplasmin, IRP1/2 iron regulatory proteins, ACSL4 acyl CoA synthetase long chain family member 4, LPCAT3 lysophosphatidylcholine acyltransferase 3, AA arachidonic acid, AdA adrenic acid, FAT fatty acid translocase, FATP fatty acid transport protein, PE phosphatidylethanolamine, PE-AA arachidonic acid-phosphatidylethanolamines, PE-AdA adrenic acid-phosphatidylethanolamines, MUFA monounsaturated fatty acid, PEBP1 phosphatidylethanolamine-binding protein 1, ALOX15 arachidonic acid-15-lipoxygenase, CEP cepharanthine, GSH glutathione, GCL glutamatecysteine ligase, GS glutathione synthetase, SLC3A2 solute carrier family 3 member 2, SLC7A11 solute carrier family 7 member 11, GPX4 glutathione peroxidase 4, FSP1 ferroptosis suppressor protein 1, NADPH nicotinamide adenine dinucleotide phosphate hydride, Nrf2 NF-E2-related factor 2, HSF1 heat shock factor 1, HSPB1 heat shock protein B1, NCOA4 nuclear receptor coactivator 4, SIRT1 sirtuin 1