Membrane Damage during Ferroptosis Is Caused by Oxidation of Phospholipids Catalyzed by the Oxidoreductases POR and CYB5R1

Lipid Metabolism and Ferroptosis

“…An independent genome-wide CRISPR/Cas9 screen also revealed that POR is a key regulator of ferroptosis [59]. In addition to POR, the ER-resident oxidoreductase, cytochrome B5 Reductase 1 (CYB5R1) is required for complete lipid peroxidation [59].…”

“…An independent genome-wide CRISPR/Cas9 screen also revealed that POR is a key regulator of ferroptosis [59]. In addition to POR, the ER-resident oxidoreductase, cytochrome B5 Reductase 1 (CYB5R1) is required for complete lipid peroxidation [59]. While a previous report showed that cytochrome P450 is an important electron acceptor for ferroptosis, this study suggests that electron acceptors, including cytochrome P450, heme oxygenase (HO-1), and squalene monooxygenase (SQLE), are dispensable for ferroptosis [59].…”

“…In addition to POR, the ER-resident oxidoreductase, cytochrome B5 Reductase 1 (CYB5R1) is required for complete lipid peroxidation [59]. While a previous report showed that cytochrome P450 is an important electron acceptor for ferroptosis, this study suggests that electron acceptors, including cytochrome P450, heme oxygenase (HO-1), and squalene monooxygenase (SQLE), are dispensable for ferroptosis [59]. Rather, POR and CYB5R1 produce H 2 O 2 by donating electrons to oxygen, triggering iron-dependent Fenton reaction and lipid peroxidation [59].…”

Ferroptosis by Lipid Peroxidation: The Tip of the Iceberg?

“…B5 type A (CYB5A), squalene epoxidase (SQLE), and heme oxygenase 1 (HMOX1/HO1), were not associated with PORmediated ferroptosis. These findings emphasize the proferroptotic synergy between POR and CYB5R1 (Yan et al, 2020), although early studies have shown that POR alone is sufficient to promote ferroptosis (Zou et al, 2020b).…”

“…However, despite this significant pathway, the process of lipid peroxidation, especially the biological source of free radicals in ferroptosis, remains poorly understood (Zou et al, 2020a). Complementing previous findings that the oxidoreductases cytochrome P450 oxidoreductase (POR) is a positive regulator of ferroptosis (Zou et al, 2020b), a recent study by Yan and colleagues demonstrated that coupling of POR to cytochrome B5 reductase 1 (CYB5R1) mediates the production of H 2 O 2 , which drives lipid peroxidation and subsequent ferroptosis through the iron-catalyzed Fenton reaction (Yan et al, 2020) (Figure 1).…”