Figure 4.

Ferroptotic signaling pathway. (A) Among phospholipids (PLs), PE-esterified AA or AdA are predominantly located in the inner leaflet of the plasma membrane or nonbilayer arrangements in contrast to the high PC confinement on the outer membrane or ordered bilayer organization of PC-PUFAs [103]. The lipid hydroperoxides (PL-PUFA-OOH or PE-AA-OOH) are detoxified to alcohol (PL-PUFA-OH or PE-AA-OH) by GPX4. On the other hand, PL-PUFA-OOH and PE-AA-OOH yield iron-mediated peroxyl (R-OO^•) or alkoxyl (R-O^•) radicals; finally, reactive electrophiles transduce lipid death signals. These ferroptotic signals are attenuated by suppressing lipid peroxidation with vitamin E or iron chelation with DFO while being enhanced by lipoxygenases (LOXs) or acyl-CoA synthetase long chain family member 4 (ACSL4) or lysophosphatidylcholine acyltransferase 3 (LPCAT3), which mediate PE esterification with PUFAs in addition to PC and phosphatidylserine (PS). The ferroptosis inhibitors are shown in red, while the ferroptosis inducers are shown in blue. (B) The compounds that trigger glutaminolysis or that inhibit the cystine/GSH/GPX4 axis, FSP1/CoQ₁₀/α-Toc (ferroptosis suppressor protein 1/coenzymeQ₁₀) axis, GCH1/BH4/DHFR (guanosine triphosphate cyclohydrolase 1/tetrahydrobiopterin/dihydrofolate reductase) axis, or NADPH synthesis are categorized as ferroptosis inducers that may initiate tumor cell death, while PUFA metabolism suppressors or iron chelators are designated as ferroptosis inhibitors that may confer the prevention of ischemic injury, neurodegeneration, or pancreatic β-cell loss. In addition to these beneficial roles of ferroptosis, the protection of tumor-initiating cells is also speculated.