Insight the mechanism of ferroptosis inhibition by ferrostatin-1

Miotto, Giovanni; Rossetto, Monica; Roveri, Antonella; Venerando, Rina; Vučković, Ana-Marija; Paolo, Maria Luisa Di; Bosello-Travain, Valentina; Zaccarin, Mattia; Maiorino, Matilde; Toppo, Stefano; Ursini, Fulvio; Cozza, Giorgio

doi:10.1016/j.freeradbiomed.2018.04.397

Cited by 40 publications

(43 citation statements)

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“…The function of Fer-1 against ferroptosis mainly depends on the inhibition of lipid peroxidation. Recently, another group indicated that the anti-ferroptotic effect of fer-1 is mainly dependent on the scavenging of initiating alkoxyl radicals and other rearrangement products [48]. We found that the expression level of HEPCIDIN in the LPS group also could be decreased by Fer-1 treatment in vitro and in vivo ( Fig.…”

Section: Discussionmentioning

confidence: 50%

Ferrostatin-1 alleviates lipopolysaccharide-induced acute lung injury via inhibiting ferroptosis

et al. 2020

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Background: Ferroptosis is a newly recognized type of cell death, which is different from traditional necrosis, apoptosis or autophagic cell death. However, the position of ferroptosis in lipopolysaccharide (LPS)-induced acute lung injury (ALI) has not been explored intensively so far. In this study, we mainly analyzed the relationship between ferroptosis and LPS-induced ALI. Methods: In this study, a human bronchial epithelial cell line, BEAS-2B, was treated with LPS and ferrostatin-1 (Fer-1, ferroptosis inhibitor). The cell viability was measured using CCK-8. Additionally, the levels of malondialdehyde (MDA), 4-hydroxynonenal (4-HNE), and iron, as well as the protein level of SLC7A11 and GPX4, were measured in different groups. To further confirm the in vitro results, an ALI model was induced by LPS in mice, and the therapeutic action of Fer-1 and ferroptosis level in lung tissues were evaluated. Results: The cell viability of BEAS-2B was down-regulated by LPS treatment, together with the ferroptosis markers SLC7A11 and GPX4, while the levels of MDA, 4-HNE and total iron were increased by LPS treatment in a dose-dependent manner, which could be rescued by Fer-1. The results of the in vivo experiment also indicated that Fer-1 exerted therapeutic action against LPS-induced ALI, and down-regulated the ferroptosis level in lung tissues. Conclusions: Our study indicated that ferroptosis has an important role in the progression of LPS-induced ALI, and ferroptosis may become a novel target in the treatment of ALI patients.

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Section: Discussionmentioning

confidence: 50%

Ferrostatin-1 alleviates lipopolysaccharide-induced acute lung injury via inhibiting ferroptosis

et al. 2020

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“…To assess the functional implication of lipid ROS or oxPLs in cell death execution, we next performed a genetic approach by overexpression GPX4 and as a pharmacological approach using the lipophilic radical trap Ferrostatin-1 (Fer1) 3 to block LPO. While GPX4 overexpression clearly inhibited the increase in lipid ROS in ferroptotic BMDMs (Supplementary Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Most ferroptosis inducers rely on blocking the activity of glutathione peroxidase 4 (GPX4)—an enzyme able to reduce PL-hydroperoxide (PL-OOH) to its alcohol form (PL-OH). Consequently, PL-OOH upon reaction with labile iron generates alkoxyl and peroxyl radicals, which further fuels oxidation of PLs (oxPLs) in cellular membranes 3 . The continued oxidation of PUFA-containing PLs is followed by thinning and increased curvature of membrane, thereby stimulating oxidative micellization, pore formation, and subsequent cell membrane rupture 4 .…”

Section: Introductionmentioning

confidence: 99%

Excessive phospholipid peroxidation distinguishes ferroptosis from other cell death modes including pyroptosis

et al. 2020

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Lipid peroxidation (LPO) drives ferroptosis execution. However, LPO has been shown to contribute also to other modes of regulated cell death (RCD). To clarify the role of LPO in different modes of RCD, we studied in a comprehensive approach the differential involvement of reactive oxygen species (ROS), phospholipid peroxidation products, and lipid ROS flux in the major prototype modes of RCD viz. apoptosis, necroptosis, ferroptosis, and pyroptosis. LC-MS oxidative lipidomics revealed robust peroxidation of three classes of phospholipids during ferroptosis with quantitative predominance of phosphatidylethanolamine species. Incomparably lower amounts of phospholipid peroxidation products were found in any of the other modes of RCD. Nonetheless, a strong increase in lipid ROS levels was detected in non-canonical pyroptosis, but only during cell membrane rupture. In contrast to ferroptosis, lipid ROS apparently was not involved in non-canonical pyroptosis execution nor in the release of IL-1β and IL-18, while clear dependency on CASP11 and GSDMD was observed. Our data demonstrate that ferroptosis is the only mode of RCD that depends on excessive phospholipid peroxidation for its cytotoxicity. In addition, our results also highlight the importance of performing kinetics and using different methods to monitor the occurrence of LPO. This should open the discussion on the implication of particular LPO events in relation to different modes of RCD.

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“…Indeed, in model systems, free radical azo-initiators oxidize various phospholipids classes independently of their headgroup [ 27 ]. Free radical peroxidation of a mixture of sn-1-stearoyl, sn-2-linoleoyl PC and PE initiated by Fe 2+ /ascorbate yielded at least 13 species of oxidized PLS (including hydroperoxy-products), and oxidatively truncated PC and PE species [ 19 ]. 7-(diethylamino)coumarin-3-carbohydrazide initiated free radical oxidation resulted in the formation of 31 oxidized species of PG, 23 species of PC-ox, 34 species of PE-ox, 7 species of PS-ox, 17 species of PA-ox and 6 species of oxidized phosphatidylinositiol phosphate (PIox) species [ 27 ].…”

Section: Discussionmentioning

confidence: 99%

“…This moiety can simultaneously interact with lipid radicals forming a planar seven-membered ring in the transition state, which displays a very high scavenging reactivity [ 18 ]. In Fe-catalyzed phospholipid peroxidation, the Fer-1 effectiveness was explained by a special mechanism of Fe-chelation by Fer-1, leading to reductive recycling of the compound by alkoxyl radical intermediates [ 19 ]. Because Fer-1 acted as a poor 15LOX inhibitor [ 11 , 16 ], it has been argued that chemical, free radical lipid peroxidation rather than enzymatic 15LOX-driven reactions is essential for the execution of the ferroptotic cell death program [ 11 , 16 ].…”

Section: Introductionmentioning

confidence: 99%

Resolving the paradox of ferroptotic cell death: Ferrostatin-1 binds to 15LOX/PEBP1 complex, suppresses generation of peroxidized ETE-PE, and protects against ferroptosis

et al. 2021

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Hydroperoxy-eicosatetraenoyl-phosphatidylethanolamine (HpETE-PE) is a ferroptotic cell death signal. HpETE-PE is produced by the 15-Lipoxygenase (15LOX)/Phosphatidylethanolamine Binding Protein-1 (PEBP1) complex or via an Fe-catalyzed non-enzymatic radical reaction. Ferrostatin-1 (Fer-1), a common ferroptosis inhibitor, is a lipophilic radical scavenger but a poor 15LOX inhibitor arguing against 15LOX having a role in ferroptosis. In the current work, we demonstrate that Fer-1 does not affect 15LOX alone, however, it effectively inhibits HpETE-PE production by the 15LOX/PEBP1 complex. Computational molecular modeling shows that Fer-1 binds to the 15LOX/PEBP1 complex at three sites and could disrupt the catalytically required allosteric motions of the 15LOX/PEBP1 complex. Using nine ferroptosis cell/tissue models, we show that HpETE-PE is produced by the 15LOX/PEBP1 complex and resolve the long-existing Fer-1 anti -ferroptotic paradox.

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Insight the mechanism of ferroptosis inhibition by ferrostatin-1

Cited by 40 publications

References 0 publications

Ferrostatin-1 alleviates lipopolysaccharide-induced acute lung injury via inhibiting ferroptosis

Ferrostatin-1 alleviates lipopolysaccharide-induced acute lung injury via inhibiting ferroptosis

Excessive phospholipid peroxidation distinguishes ferroptosis from other cell death modes including pyroptosis

Resolving the paradox of ferroptotic cell death: Ferrostatin-1 binds to 15LOX/PEBP1 complex, suppresses generation of peroxidized ETE-PE, and protects against ferroptosis

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