TY  - JOUR
AB  - Ferroptosis is an iron-dependent form of regulated cell death linking iron, lipid, and glutathione levels to degenerative processes and tumor suppression. By performing a genome-wide activation screen, we identified a cohort of genes antagonizing ferroptotic cell death, including GTP cyclohydrolase-1 (GCH1) and its metabolic derivatives tetrahydrobiopterin/dihydrobiopterin (BH4/BH2). Synthesis of BH4/BH2 by GCH1-expressing cells caused lipid remodeling, suppressing ferroptosis by selectively preventing depletion of phospholipids with two polyunsaturated fatty acyl tails. GCH1 expression level in cancer cell lines stratified susceptibility to ferroptosis, in accordance with its expression in human tumor samples. The GCH1-BH4-phospholipid axis acts as a master regulator of ferroptosis resistance, controlling endogenous production of the antioxidant BH4, abundance of CoQ(10), and peroxidation of unusual phospholipids with two polyunsaturated fatty acyl tails. This demonstrates a unique mechanism of ferroptosis protection that is independent of the GPX4/glutathione system.
AU  - Kraft, V.
AU  - Bezjian, C.T.*
AU  - Pfeiffer, S.
AU  - Ringelstetter, L.
AU  - Müller, C.
AU  - Zandkarimi, F.*
AU  - Merl-Pham, J.
AU  - Bao, X.
AU  - Anastasov, N.
AU  - Kössl, J.
AU  - Brandner, S.
AU  - Daniels, J.D.*
AU  - Schmitt-Kopplin, P.
AU  - Hauck, S.M.
AU  - Stockwell, B.R.*
AU  - Hadian, K.
AU  - Schick, J.
C1  - 57834
C2  - 47948
CY  - 1155 16th St, Nw, Washington, Dc 20036 Usa
SP  - 41-53
TI  - GTP cyclohydrolase 1/tetrahydrobiopterin counteract ferroptosis through lipid remodeling.
JO  - ACS Cent. Sci.
VL  - 6
IS  - 1
PB  - Amer Chemical Soc
PY  - 2020
SN  - 2374-7943
ER  - 

TY  - JOUR
AU  - Friedmann Angeli, J.P.F.
AU  - Conrad, M.
C1  - 53425
C2  - 44728
CY  - Washington
SP  - 312-314
TI  - Lipoxygenases-killers against their will?
JO  - ACS Cent. Sci.
VL  - 4
IS  - 3
PB  - Amer Chemical Soc
PY  - 2018
SN  - 2374-7943
ER  - 

TY  - JOUR
AB  - Ferroptosis is a form of regulated necrosis associated with the iron-dependent accumulation of lipid hydroperoxides that may play a key role in the pathogenesis of degenerative diseases in which lipid peroxidation has been implicated. High-throughput screening efforts have identified ferrostatin-1 (Fer-1) and liproxstatin-1 (Lip-1) as potent inhibitors of ferroptosis - an activity that has been ascribed to their ability to slow the accumulation of lipid hydroperoxides. Herein we demonstrate that this activity likely derives from their reactivity as radical-trapping antioxidants (RTAs) rather than their potency as inhibitors of lipoxygenases. Although inhibited autoxidations of styrene revealed that Fer-1 and Lip-1 react roughly 10-fold more slowly with peroxyl radicals than reactions of α-tocopherol (α-TOH), they were significantly more reactive than α-TOH in phosphatidylcholine lipid bilayers - consistent with the greater potency of Fer-1 and Lip-1 relative to α-TOH as inhibitors of ferroptosis. None of Fer-1, Lip-1, and α-TOH inhibited human 15-lipoxygenase-1 (15-LOX-1) overexpressed in HEK-293 cells when assayed at concentrations where they inhibited ferroptosis. These results stand in stark contrast to those obtained with a known 15-LOX-1 inhibitor (PD146176), which was able to inhibit the enzyme at concentrations where it was effective in inhibiting ferroptosis. Given the likelihood that Fer-1 and Lip-1 subvert ferroptosis by inhibiting lipid peroxidation as RTAs, we evaluated the antiferroptotic potential of 1,8-tetrahydronaphthyridinols (hereafter THNs): rationally designed radical-trapping antioxidants of unparalleled reactivity. We show for the first time that the inherent reactivity of the THNs translates to cell culture, where lipophilic THNs were similarly effective to Fer-1 and Lip-1 at subverting ferroptosis induced by either pharmacological or genetic inhibition of the hydroperoxide-detoxifying enzyme Gpx4 in mouse fibroblasts, and glutamate-induced death of mouse hippocampal cells. These results demonstrate that potent RTAs subvert ferroptosis and suggest that lipid peroxidation (autoxidation) may play a central role in the process.
AU  - Zilka, O.*
AU  - Shah, R.*
AU  - Li, B.*
AU  - Friedmann Angeli, J.P.F.
AU  - Griesser, M.*
AU  - Conrad, M.
AU  - Pratt, D.A.*
C1  - 50907
C2  - 42997
SP  - 232-243
TI  - On the mechanism of cytoprotection by ferrostatin-1 and liproxstatin-1 and the role of lipid peroxidation in ferroptotic cell death.
JO  - ACS Cent. Sci.
VL  - 3
IS  - 3
PY  - 2017
SN  - 2374-7943
ER  -