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Signal Transduction and Targeted Therapy Feb 2021Ferroptosis is an iron-dependent cell death, which is different from apoptosis, necrosis, autophagy, and other forms of cell death. The process of ferroptotic cell death... (Review)
Review
Ferroptosis is an iron-dependent cell death, which is different from apoptosis, necrosis, autophagy, and other forms of cell death. The process of ferroptotic cell death is defined by the accumulation of lethal lipid species derived from the peroxidation of lipids, which can be prevented by iron chelators (e.g., deferiprone, deferoxamine) and small lipophilic antioxidants (e.g., ferrostatin, liproxstatin). This review summarizes current knowledge about the regulatory mechanism of ferroptosis and its association with several pathways, including iron, lipid, and cysteine metabolism. We have further discussed the contribution of ferroptosis to the pathogenesis of several diseases such as cancer, ischemia/reperfusion, and various neurodegenerative diseases (e.g., Alzheimer's disease and Parkinson's disease), and evaluated the therapeutic applications of ferroptosis inhibitors in clinics.
Topics: Alzheimer Disease; Apoptosis; Autophagy; Cysteine; Ferroptosis; Humans; Iron; Lipid Metabolism; Lipid Peroxidation; Neoplasms; Parkinson Disease; Reactive Oxygen Species
PubMed: 33536413
DOI: 10.1038/s41392-020-00428-9 -
Acta Pharmaceutica Sinica. B Feb 2022Herein, we define the role of ferroptosis in the pathogenesis of diabetic cardiomyopathy (DCM) by examining the expression of key regulators of ferroptosis in mice with...
Herein, we define the role of ferroptosis in the pathogenesis of diabetic cardiomyopathy (DCM) by examining the expression of key regulators of ferroptosis in mice with DCM and a new DCM model. Advanced glycation end-products (AGEs), an important pathogenic factor of DCM, were found to induce ferroptosis in engineered cardiac tissues (ECTs), as reflected through increased levels of and lipid peroxides and decreased ferritin and SLC7A11 levels. Typical morphological changes of ferroptosis in cardiomyocytes were observed using transmission electron microscopy. Inhibition of ferroptosis with ferrostatin-1 and deferoxamine prevented AGE-induced ECT remodeling and dysfunction. Ferroptosis was also evidenced in the heart of type 2 diabetic mice with DCM. Inhibition of ferroptosis by liproxstatin-1 prevented the development of diastolic dysfunction at 3 months after the onset of diabetes. Nuclear factor erythroid 2-related factor 2 (NRF2) activated by sulforaphane inhibited cardiac cell ferroptosis in both AGE-treated ECTs and hearts of DCM mice by upregulating ferritin and SLC7A11 levels. The protective effect of sulforaphane on ferroptosis was AMP-activated protein kinase (AMPK)-dependent. These findings suggest that ferroptosis plays an essential role in the pathogenesis of DCM; sulforaphane prevents ferroptosis and associated pathogenesis AMPK-mediated NRF2 activation. This suggests a feasible therapeutic approach with sulforaphane to clinically prevent ferroptosis and DCM.
PubMed: 35256941
DOI: 10.1016/j.apsb.2021.10.005 -
International Journal of Molecular... Feb 2022Ferroptosis has been previously implicated in the pathological progression of cardiomyopathy. Herceptin (trastuzumab), which targets HER2, is commonly applied for the...
Ferroptosis has been previously implicated in the pathological progression of cardiomyopathy. Herceptin (trastuzumab), which targets HER2, is commonly applied for the treatment of HER2 breast cancer. However, its clinical use is limited by its cardiotoxicity. Therefore, the present study aimed to investigate if targeting ferroptosis could protect against Herceptin‑induced heart failure in an model of H9c2 cells after treatment of Herceptin, Herceptin + ferroptosis inhibitor ferrostatin‑1 (Fer‑1) or Herceptin + Deferoxamine. H9c2 cell viability was measured by MTT assay. Reactive oxygen species (ROS) levels were detected by measuring the fluorescence of DCFH‑DA‑A and MitoSOX™ Red. Glutathione (GSH)/oxidized glutathione (GSSG) ratio was measured using the GSH/GSSG Ratio Detection Assay kit. Mitochondrial membrane potential and ATP content were evaluated by JC‑1 staining and bioluminescent assay kits, respectively. Protein expressions of glutathione peroxidase 4, recombinant solute carrier family 7 member 11, mitochondrial optic atrophy1‑1/2, mitofusin, Acyl‑CoA synthetase long chain family member 4, cytochrome , voltage‑dependent anion‑selective channel, dynamin‑related protein, mitochondrial fission 1 protein and mitochondrial ferritin were evaluated by western blotting. It was found that Herceptin reduced H9c2 cell viability whilst increasing intracellular and mitochondrial ROS levels in a dose‑ and time‑dependent manner. Furthermore, Herceptin decreased glutathione peroxidase (GPX) protein expression and the GSH/ GSSG ratio in H9c2 cells in a dose‑ and time‑dependent manner. The Fer‑1 abolished this Herceptin‑induced reduction in cell viability, GSH/GSSG ratio, mitochondrial membrane potential and ATP content. Fer‑1 also reversed the suppressive effects of Herceptin on the protein expression levels of GPX4, recombinant solute carrier family 7 member 11, mitochondrial optic atrophy1‑1/2 and mitofusin in H9c2 cells. Subsequently, Fer‑1 was found to reverse the Herceptin‑induced increase in mitochondrial ROS and iron levels in H9c2 cells, as well as the increased protein expression levels of Acyl‑CoA synthetase long chain family member 4, cytochrome , voltage‑dependent anion‑selective channel, dynamin‑related protein, mitochondrial fission 1 protein and mitochondrial ferritin in H9c2 cells. However, compared with deferoxamine, an iron chelator, the effects of Fer‑1 were less effective. Collectively, these findings provided insights into the pathogenic mechanism that underlie Herceptin‑induced cardiomyopathy, which potentially provides a novel therapeutic target for the prevention of cardiotoxicity in HER2 breast cancer treatment.
Topics: Animals; Cell Line; Cyclohexylamines; Cytoprotection; Ferroptosis; Mitochondria; Oxidative Stress; Phenylenediamines; Rats; Trastuzumab
PubMed: 34935058
DOI: 10.3892/ijmm.2021.5072 -
Autophagy Jul 2023Ferroptosis is a newly characterized form of programmed cell death, which is driven by the lethal accumulation of lipid peroxides catalyzed by the intracellular...
Ferroptosis is a newly characterized form of programmed cell death, which is driven by the lethal accumulation of lipid peroxides catalyzed by the intracellular bioactive iron. Targeted induction of ferroptotic cell death holds great promise for therapeutic design against other therapy-resistant cancers. To date, multiple post-translational modifications have been elucidated to impinge on the ferroptotic sensitivity. Here we report that the Ser/Thr protein kinase ATM, the major sensor of DNA double-strand break damage, is indispensable for ferroptosis execution. Pharmacological inhibition or genetic ablation of ATM significantly antagonizes ferroptosis. Besides, ATM ablation-induced ferroptotic resistance is largely independent of its downstream target TRP53, as cells defective in both and are still more insensitive to ferroptotic inducers than the single knockout cells. Mechanistically, ATM dominates the intracellular labile free iron by phosphorylating NCOA4, facilitating NCOA4-ferritin interaction and therefore sustaining ferritinophagy, a selective type of macroautophagy/autophagy specifically degrading ferritin for iron recycling. Our results thus uncover a novel regulatory circuit of ferroptosis comprising ATM-NCOA4 in orchestrating ferritinophagy and iron bioavailability. AMPK: AMP-activated protein kinase; ATM: ataxia telangiectasia mutated; BSO: buthionine sulphoximine; CDKN1A: cyclin-dependent kinase inhibitor 1A (P21); CQ: chloroquine; DFO: deferoxamine; DFP: deferiprone; Fer: ferrostatin-1; FTH1: ferritin heavy polypeptide 1; GPX4: glutathione peroxidase 4; GSH: glutathione; MEF: mouse embryonic fibroblast; NCOA4: nuclear receptor coactivator 4; PFTα: pifithrin-α; PTGS2: prostaglandin-endoperoxide synthase 2; Slc7a11: solute carrier family 7 member 11; Sul: sulfasalazine; TFRC: transferrin receptor; TRP53: transformation related protein 53.
Topics: Animals; Mice; Ferroptosis; Autophagy; Fibroblasts; Transcription Factors; Ferritins; Iron; Buthionine Sulfoximine
PubMed: 36752571
DOI: 10.1080/15548627.2023.2170960 -
Nutrients Jan 2023Iron functions as an essential micronutrient and participates in normal physiological and biochemical processes in the cardiovascular system. Ferroptosis is a novel type... (Review)
Review
Iron functions as an essential micronutrient and participates in normal physiological and biochemical processes in the cardiovascular system. Ferroptosis is a novel type of iron-dependent cell death driven by iron accumulation and lipid peroxidation, characterized by depletion of glutathione and suppression of glutathione peroxidase 4 (GPX4). Dysregulation of iron metabolism and ferroptosis have been implicated in the occurrence and development of cardiovascular diseases (CVDs), including hypertension, atherosclerosis, pulmonary hypertension, myocardial ischemia/reperfusion injury, cardiomyopathy, and heart failure. Iron chelators deferoxamine and dexrazoxane, and lipophilic antioxidants ferrostatin-1 and liproxstatin-1 have been revealed to abolish ferroptosis and suppress lipid peroxidation in atherosclerosis, cardiomyopathy, hypertension, and other CVDs. Notably, inhibition of ferroptosis by ferrostatin-1 has been demonstrated to alleviate cardiac impairments, fibrosis and pathological remodeling during hypertension by potentiating GPX4 signaling. Administration of deferoxamine improved myocardial ischemia/reperfusion injury by inhibiting lipid peroxidation. Several novel small molecules may be effective in the treatment of ferroptosis-mediated CVDs. In this article, we summarize the regulatory roles and underlying mechanisms of iron metabolism dysregulation and ferroptosis in the occurrence and development of CVDs. Targeting iron metabolism and ferroptosis are potential therapeutic strategies in the prevention and treatment of hypertension and other CVDs.
Topics: Humans; Ferroptosis; Cardiovascular Diseases; Myocardial Reperfusion Injury; Deferoxamine; Lipid Peroxidation; Iron; Hypertension
PubMed: 36771298
DOI: 10.3390/nu15030591 -
Frontiers in Pharmacology 2022Osteoarthritis (OA) is a common disease with a complex pathology including mechanical load, inflammation, and metabolic factors. Chondrocyte ferroptosis contributes to...
Osteoarthritis (OA) is a common disease with a complex pathology including mechanical load, inflammation, and metabolic factors. Chondrocyte ferroptosis contributes to OA progression. Because iron deposition is a major pathological event in ferroptosis, deferoxamine (DFO), an effective iron chelator, has been used to inhibit ferroptosis in various degenerative disease models. Nevertheless, its OA treatment efficacy remains unknown. We aimed to determine whether DFO alleviates chondrocyte ferroptosis and its effect on OA and to explore its possible mechanism. Interleukin-1β (IL-1β) was used to simulate inflammation, and chondrocyte ferroptosis was induced by erastin, a classic ferroptosis inducer. A surgical destabilized medial meniscus mouse model was also applied to simulate OA , and erastin was injected into the articular cavity to induce mouse knee chondrocyte ferroptosis. We determined the effects of DFO on ferroptosis and injury-related events: chondrocyte inflammation, extracellular matrix degradation, oxidative stress, and articular cartilage degradation. IL-1β increased the levels of ROS, lipid ROS, and the lipid peroxidation end product malondialdehyde (MDA) and altered ferroptosis-related protein expression in chondrocytes. Moreover, ferrostatin-1 (Fer-1), a classic ferroptosis inhibitor, rescued the IL-1β-induced decrease in collagen type II (collagen II) expression and increase in matrix metalloproteinase 13 (MMP13) expression. Erastin promoted MMP13 expression in chondrocytes but inhibited collagen II expression. DFO alleviated IL-1β- and erastin-induced cytotoxicity in chondrocytes, abrogated ROS and lipid ROS accumulation and the increase in MDA, improved OA-like changes in chondrocytes, and promoted nuclear factor E2-related factor 2 (Nrf2) antioxidant system activation. Finally, intra-articular injection of DFO enhanced collagen II expression in OA model mice, inhibited erastin-induced articular chondrocyte death, and delayed articular cartilage degradation and OA progression. Our research confirms that ferroptosis occurs in chondrocytes under inflammatory conditions, and inhibition of chondrocyte ferroptosis can alleviate chondrocyte destruction. Erastin-induced chondrocyte ferroptosis can stimulate increased MMP13 expression and decreased collagen II expression in chondrocytes. DFO can suppress chondrocyte ferroptosis and promote activation of the Nrf2 antioxidant system, which is essential for protecting chondrocytes. In addition, ferroptosis inhibition by DFO injection into the articular cavity may be a new OA treatment.
PubMed: 35359876
DOI: 10.3389/fphar.2022.791376 -
Acta Pharmaceutica Sinica. B Dec 2021Ferroptosis is a non-apoptotic regulated cell death caused by iron accumulation and subsequent lipid peroxidation. Currently, the therapeutic role of ferroptosis on...
Ferroptosis is a non-apoptotic regulated cell death caused by iron accumulation and subsequent lipid peroxidation. Currently, the therapeutic role of ferroptosis on cancer is gaining increasing interest. Baicalin an active component in Georgi with anticancer potential various cancer types; however, the effects of baicalein on bladder cancer and the underlying molecular mechanisms remain largely unknown. In the study, we investigated the effect of baicalin on bladder cancer cells 5637 and KU-19-19. As a result, we show baicalin exerted its anticancer activity by inducing apoptosis and cell death in bladder cancer cells. Subsequently, we for the first time demonstrate baicalin-induced ferroptotic cell death and , accompanied by reactive oxygen species (ROS) accumulation and intracellular chelate iron enrichment. The ferroptosis inhibitor deferoxamine but not necrostatin-1, chloroquine (CQ), -acetyl-l-cysteine, l-glutathione reduced, or carbobenzoxy-valyl-alanyl-aspartyl-[-methyl]-fluoromethylketone (Z-VAD-FMK) rescued baicalin-induced cell death, indicating ferroptosis contributed to baicalin-induced cell death. Mechanistically, we show that ferritin heavy chain 1 (FTH1) was a key determinant for baicalin-induced ferroptosis. Overexpression of FTH1 abrogated the anticancer effects of baicalin in both 5637 and KU19-19 cells. Taken together, our data for the first time suggest that the natural product baicalin exerts its anticancer activity by inducing FTH1-dependent ferroptosis, which will hopefully provide a prospective compound for bladder cancer treatment.
PubMed: 35024325
DOI: 10.1016/j.apsb.2021.03.036 -
Cell Death & Disease Jul 2022Endometriosis (EMs) occurs in approximately 50% of women with infertility. The main causes of EMs-related infertility are follicle dysplasia and reduced oocyte quality....
Endometriosis (EMs) occurs in approximately 50% of women with infertility. The main causes of EMs-related infertility are follicle dysplasia and reduced oocyte quality. Iron overload occurs in ovarian follicular fluid (FF) of patients with EMs, and this condition is associated with oocyte maturation disorder. However, the underlying molecular mechanism remains largely unknown. In the present study, we identified the mechanism underlying ferroptosis in ovarian granulosa cells and oocyte maturation failure in EMs based on a retrospective review of in vitro fertilization/intracytoplasmic sperm injection-frozen embryo transfer outcomes in infertile patients with EMs. Mouse granulosa cells were treated with EMs-related infertile patients' follicular fluid (EMFF) in vitro. Western blot analysis, quantitative polymerase chain reaction, fluorescence staining, and transmission electron microscopy were used to assess granulosa cells ferroptosis. The effects of exosomes were examined by nanoparticle tracking analysis, RNA-seq, and Western blot analysis. Finally, the therapeutic values of vitamin E and iron chelator (deferoxamine mesylate) in vivo were evaluated in an EMs-related infertility model. Patients with ovarian EMs experienced poorer oocyte fertility than patients with non-ovarian EMs. We observed that EMFF with iron overload-induced granulosa cell ferroptosis in vitro and in vivo. Mechanically, nuclear receptor coactivator four-dependent ferritinophagy was involved in this process. Notably, granulosa cells undergoing ferroptosis further suppressed oocyte maturation by releasing exosomes from granulosa cells. In therapeutic studies, vitamin E and iron chelators effectively alleviated EMs-related infertility models. Our study indicates a novel mechanism through which EMFF with iron overload induces ferroptosis of granulosa cells and oocyte dysmaturity in EMs-related infertility, providing a potential therapeutic strategy for EMs-related infertility.
Topics: Animals; Deferoxamine; Endometriosis; Female; Ferroptosis; Follicular Fluid; Granulosa Cells; Humans; Infertility, Female; Iron; Iron Overload; Mice; Oocytes; Vitamin E
PubMed: 35787614
DOI: 10.1038/s41419-022-05037-8