Ferroptosis requires iron overload. The iron in the circulation of the human body exists in the form of Fe
3+. Fe
3+ is imported into the cell by transferrin and transferrin receptor 1 (TfR1)
[7,11][6][7] then reduced to Fe
2+ in the lysosome and, finally, released to the labile iron pool through the divalent metal 9 transporter 1 (DMT1) or zinc iron regulatory protein family 8/14 (ZIP8/14)
[33,34][8][9]. Excess iron in cells is usually stored in ferritin
[35][10], and ferritin can be recognized by the specific cargo receptor NCOA4, which recruits ferritin to autophagosomes for lysosomal degradation and releases Fe
2+ [35,36,37,38][10][11][12][13]. The released Fe
2+ will generate ROS through the Fenton reaction, and then undergoes a peroxidation reaction with lipids to trigger ferroptosis
[29][2]. Increased iron absorption and reduced iron storage can lead to iron overload. Therefore, inhibiting iron overload by iron chelating agents can inhibit ferroptosis, and silencing the iron metabolism master regulator, iron responsive element binding protein 2 (IREB2), can also reduce the sensitivity of cells to ferroptosis
[8][1].
In addition to abnormal iron metabolism, lipid peroxidation is also an important factor leading to ferroptosis. Lipidomic analysis showed that phosphatidylethanolamines (PEs) containing arachidonic acid (AA) or adrenal acid (AdA) are the key membrane phospholipids, which can be oxidized to phospholipid hydroperoxides (PE-AA/AdA-OOH) through non-enzymatic reactions, thereby driving ferroptosis
[39,40][14][15]. The main ROS accumulated in cells are superoxide radical anions (·O
2−) and hydrogen peroxide (H
2O
2). In the presence of free iron, these ROS may be converted into hydroxyl radicals (HO˙), which are highly reactive to PUFAs that exist in a variety of cell membranes
[41][16]. Free PUFAs, including AA, are oxidized through a catalytic pathway involving acyl-CoA synthetase long-chain family member 4 (ACSL4), lysophosphatidylcholine acyltransferase 3 (LPCAT3), and lipoxygenase (LOXs)
[42,43][17][18]. ACSL4 and LPCAT3 are key regulators of PUFA-PL biosynthesis
[40][15]. ACSL4 acetylates PUFA to form PUFA-CoA, and then LPCAT3 inserts PUFA-CoA into lysophospholipid to form PUFA-PL
[44][19]. Enzymatic lipid peroxidation is mainly regulated by the LOX family. LOXs can also oxidize PUFAs into corresponding phospholipid hydroperoxides, among which LOX5 and LOX12/15 are involved in ferroptosis
[45][20]. It has been reported that phosphatidylethanolamine binding protein 1 (PEBP1) can form a complex with LOX15 and act as a scaffold protein to positively regulate ferroptosis
[46][21]. It is worth noting here that 15-hydroperoxy (Hp)-arachidonoyl-phosphatidylethanolamine (15-HpETE-PE) produced by the 15-LOX/PEBP1 complex can be eliminated by Ca
2+-independent phospholipase A2β (iPLA2β)
[47][22]. This indicates that iPLA2β can act as an anti-ferroptotic guardian to regulate the intracellular ferroptosis signaling pathway, which has an important regulatory role in neurodegenerative diseases
[47][22].