On the Mechanism of Cytoprotection by Ferrostatin-1 and Liproxstatin-1 and the Role of Lipid Peroxidation in Ferroptotic Cell Death

By Omkar Zilka, Ron Shah, Bo Li, J. P. Friedmann Angeli, M. Griesser, M. Conrad, D. Pratt. ACS Central Science, 2017

910 citations recorded by the source corpus.

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.

View Paper: https://www.semanticscholar.org/paper/f0880e42a57109dbc264afe98f2aa6035c5b23bc

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Citations in the corpus

• Ferroptosis: A Regulated Cell Death Nexus Linking Metabolism, Redox Biology, and Disease. (2017, unknown): “Similarly, ferrostatins and liproxstatins inhibit lipid peroxidation, possibly by acting as radical-trapping antioxidants (Zilka et al., 2017), similarly to the lipophilic antioxidants BHT, BHA and vitamin E.”
• Ferroptosis: mechanisms and links with diseases (2021, background): “On the oxidation pathway, lipoxygenases (Lox) catalyze PUFA oxidation via a phosphorylase kinase G2 (PHKG2)-dependent iron pool,(19) whereas compounds with RTA activity ameliorate ferroptosis via blocking lipid autoxidation.(20) In 2017, it was shown that acyl-CoA synthetase long-chain family member”
• FINO2 Initiates Ferroptosis Through GPX4 Inactivation and Iron Oxidation (2018, unknown): “Despite the apparent importance of iron to FINO 2 lethality, FINO 2 treated cells did not show changes in the abundance of the iron regulatory proteins IRP2, FTL1, or TFR (Supplementary Figure 13), suggesting that FINO 2 may engage labile cellular iron preferentially over iron-containing proteins.”
• Imidazole ketone erastin induces ferroptosis and slows tumor growth in a mouse lymphoma model (2019, background): “We further tested the degree of IKE-induced lethality upon co-treatment with the ferroptosis inhibitor fer-1, a radical-trapping antioxidant that inhibits lethal lipid peroxidation during ferroptosis (Skouta et al., 2014; Zilka et al., 2017).”
• Mitochondria-dependent ferroptosis plays a pivotal role in doxorubicin cardiotoxicity (2020, unknown): “inhibitors are suppressors of lipid peroxidation, such as RTAs (10, 11).”
• The Tumor Suppressor Protein p53 and the Ferroptosis Network (2018, unknown): “Of note, the anti-ferroptosis activation of ferrostatin-1 and liproxstatin-1 (another widely-used ferroptosis inhibitor) are mediated through their reactivity as radical-trapping antioxidants rather than their potency as inhibitors of lipoxygenases [68].”
• Ferroptosis turns 10: Emerging mechanisms, physiological functions, and therapeutic applications. (2022, unknown): “Early after the discovery of ferroptosis, several potential uses of the first inhibitors of this process were reported: ferrostatin-1 and liproxstatin were found to act as radical trapping agents to inhibit the propagation of lipid peroxidation (Zilka et al., 2017) and to be effective in models of G”