Beyond ferrostatin-1: a comprehensive review of ferroptosis inhibitors

Scarpellini, Camilla; Klejborowska, Greta; Lanthier, Caroline; Hassannia, Behrouz; Vanden Berghe, Tom; Augustyns, Koen

doi:10.1016/j.tips.2023.08.012

Cited by 54 publications

(22 citation statements)

References 90 publications

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“…To further verify the specific role of ferroptosis, HK-2 cells were treated with two classical ferroptosis inhibitors, Fer-1 and DFO, in the CIN cell model [ 21 ] ( Figure 3 A,B). Fer-1 is a synthetic antioxidant that prevents membrane lipid damage through a reduction mechanism, thereby inhibiting cell death during ferroptosis.…”

Section: Resultsmentioning

confidence: 99%

Tetramethylpyrazine attenuates renal tubular epithelial cell ferroptosis in contrast-induced nephropathy by inhibiting transferrin receptor and intracellular reactive oxygen species

Zhu,

Li,

Song

et al. 2024

Clinical Science

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Contrast-induced nephropathy (CIN) is a leading cause of hospital-acquired acute kidney injury (AKI). Recently ferroptosis was reported to be crucial for AKI pathogenesis. Our previous studies indicated antioxidant tetramethylpyrazine (TMP) prevent CIN in vivo. However, whether ferroptosis is involved in TMP nephroprotective mechanism against CIN is unclear. In present study we investigated the role of renal tubular epithelial cell ferroptosis in TMP reno-protective effect against CIN and the molecular mechanisms by which TMP regulates ferroptosis. Classical contrast-medium Iohexol was used to construct CIN models in rats and HK-2 cells. Results showed tubular cell injury was accompanied by ferroptosis both in vivo and in vitro, including the typical features of ferroptosis, Fe2+ accumulation, lipid peroxidation and decreased glutathione peroxidase 4 (GPX4). Ferroptosis inhibition by classic inhibitors Fer-1 and DFO promoted cell viability and reduced intracellular ROS production. Additionally, TMP significantly inhibited renal dysfunction, reduced AKI biomarkers, prevented ROS production, inhibited renal Fe2+ accumulation and increased GPX4 expression. Expressions of various proteins associated with iron ion metabolism, including transferrin receptor (TFRC), divalent metal transporter 1, iron-responsive element binding protein 2, ferritin heavy chain 1, ferroportin 1, and heat shock factor binding protein 1, were examined using mechanistic analyses. Among these, TFRC changes were the most significant after TMP pretreatment. Results of siRNA knockdown and plasmid overexpression of TFRC indicated TFRC is essential for TMP to alleviate ferroptosis and reduce LDH release, Fe2+ accumulation and intracellular ROS. Our findings provide crucial insights about the potential of TMP in treating AKI associated with ferroptosis.

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Section: Resultsmentioning

confidence: 99%

Tetramethylpyrazine attenuates renal tubular epithelial cell ferroptosis in contrast-induced nephropathy by inhibiting transferrin receptor and intracellular reactive oxygen species

Zhu,

Li,

Song

et al. 2024

Clinical Science

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“…Nonetheless, Fer-1 has also been demonstrated to reduce the cellular LIP [ 126 ]. Liproxstatin (Lip-1) was identified in a similar way and behaves as an antioxidant cytoprotector [ 127 , 128 ]. Both Fer-1 and Lip-1 are much more effective antioxidants than vitamin E in experimental models, and their mechanism of action has underscored again the role of lipid autooxidation during ferroptosis [ 129 ].…”

Section: Molecular Mechanisms Of Ferroptosismentioning

confidence: 99%

Insight into Iron, Oxidative Stress and Ferroptosis: Therapy Targets for Approaching Anticancer Strategies

Piccolo,

Ferraro,

Iazzetti

et al. 2024

Cancers

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Based on the multifaceted molecular machinery that tightly controls iron cellular homeostasis, this review delves into its paradoxical, potentially dangerous role in biological systems, with a special focus on double-edged sword correlations with cancer. Indeed, though iron is a vital micronutrient and a required cofactor participating in several essential cell functions, its tendency to cause oxidative stress can be related both to cancer risk and to the activation of cancer cell death pathways. In this scenario, ferroptosis refers to an iron-dependent form of regulated cell death (RCD) powered by an overload of lethal peroxides sharing distinctive oxidized phospholipid profiles. As a unique cell death pathway, ferroptosis is both morphologically and mechanistically different from other types of programmed cell death involving executioner family proteins. The accumulation of cytotoxic lipid peroxides encompasses a cellular antagonism between ferroptosis execution and defense systems, with iron-dependent death occurring when ferroptosis-promoting activities significantly exceed the cellular antioxidant defenses. The most recent molecular breakthroughs in the execution of ferroptosis have aroused great consideration in tumor biology, as targeting ferroptosis can provide new tools for exploring therapeutic strategies for tumor suppression. Mutations and death/survival pathway alterations, as well as distinctive metabolic regulations of cancer cells, including the propensity to generate ROS, are seen as features that can render cancer cells unprotected to ferroptosis, thereby exposing vulnerabilities which deserve further attention to be regarded as targetable for cancers with limited therapeutic options.

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“…Extension and completion of the autophagosome membrane is not possible without LC3B-II. After fusion of the autophagosome with the lysosome, small molecules produced by degradation, particularly amino acids, are translocated back to the cytoplasm for protein synthesis and to maintain cellular function under starvation conditions [ 194 , 195 ] ATG, LC3, P62 Ferroptosis Mitochondria are small and crumpled, cristae are reduced, nuclei are normal, and cell membranes are ruptured [ 196 ] Iron ion accumulation, reactive oxygen species accumulation, lipid metabolism imbalance [ 197 ] Ferrostatin-1, Liprostatin-1, DFO, NAC, Trolox [ 198 – 201 ] In the presence of divalent iron or ester oxygenase, which catalyzes the high expression of unsaturated fatty acids on the cell membrane, lipid peroxidation occurs, resulting in the induction of cell death; in addition, a decrease in GPX4, a core enzyme in the regulation of the antioxidant system (the glutathione system), is also manifested [ 195 – 202 ] SLC7A11, GPX4, FSP1, ACSL4, PTGS2, NRF2 Morphological alterations, triggering factors, classical inhibitors, molecular mechanisms and core targets of different programmed cell deaths. …”

Section: Introductionmentioning

confidence: 99%

Ferroptosis: a new hunter of hepatocellular carcinoma

Jiang,

Yu,

Pan

et al. 2024

Cell Death Discov.

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Ferroptosis is an iron ion-dependent, regulatory cell death modality driven by intracellular lipid peroxidation that plays a key role in the development of HCC. Studies have shown that various clinical agents (e.g., sorafenib) have ferroptosis inducer-like effects and can exert therapeutic effects by modulating different key factors in the ferroptosis pathway. This implies that targeting tumor cell ferroptosis may be a very promising strategy for tumor therapy. In this paper, we summarize the prerequisites and defense systems for the occurrence of ferroptosis and the regulatory targets of drug-mediated ferroptosis action in HCC, the differences and connections between ferroptosis and other programmed cell deaths. We aim to summarize the theoretical basis, classical inducers of ferroptosis and research progress of ferroptosis in HCC cells, clued to the treatment of HCC by regulating ferroptosis network. Further investigation of the specific mechanisms of ferroptosis and the development of hepatocellular carcinoma and interventions at different stages of hepatocellular carcinoma will help us to deepen our understanding of hepatocellular carcinoma, with a view to providing new and more precise preventive as well as therapeutic measures for patients.

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Beyond ferrostatin-1: a comprehensive review of ferroptosis inhibitors

Cited by 54 publications

References 90 publications

Tetramethylpyrazine attenuates renal tubular epithelial cell ferroptosis in contrast-induced nephropathy by inhibiting transferrin receptor and intracellular reactive oxygen species

Tetramethylpyrazine attenuates renal tubular epithelial cell ferroptosis in contrast-induced nephropathy by inhibiting transferrin receptor and intracellular reactive oxygen species

Insight into Iron, Oxidative Stress and Ferroptosis: Therapy Targets for Approaching Anticancer Strategies

Ferroptosis: a new hunter of hepatocellular carcinoma

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