RESUMO
BACKGROUND: Ferroptosis, a form of programmed cell death featured by lipid peroxidation, has been proposed as a potential etiology for postoperative cognitive dysfunction (POCD). Myocyte-specific enhancer factor 2C (MEF2C), a transcription factor expressed in various brain cell types, has been implicated in cognitive disorders. This study sought to ascertain whether MEF2C governs postoperative cognitive capacity by affecting ferroptosis. METHODS: Transcriptomic analysis of public data was used to identify MEF2C as a candidate differentially expressed gene in the hippocampus of POCD mice. The POCD mouse model was established via aseptic laparotomy under isoflurane anesthesia after treatment with recombinant adeno-associated virus 9 (AAV9)-mediated overexpression of MEF2C and/or the glutathione peroxidase 4 (GPX4) inhibitor RSL3. Cognitive performance, Nissl staining, and ferroptosis-related parameters were assessed. Dual-luciferase reporter gene assays and chromatin immunoprecipitation assays were implemented to elucidate the mechanism by which MEF2C transcriptionally activates GPX4. RESULTS: MEF2C mRNA and protein levels decreased in the mouse hippocampus following anesthesia and surgery. MEF2C overexpression ameliorated postoperative memory decline, hindered lipid peroxidation and iron accumulation, and enhanced antioxidant capacity, which were reversed by RSL3. Additionally, MEF2C was found to directly bind to the Gpx4 promoter and activate its transcription. CONCLUSIONS: Our findings suggest that MEF2C may be a promising therapeutic target for POCD through its negative modulation of ferroptosis.
Assuntos
Ferroptose , Fatores de Transcrição MEF2 , Camundongos Endogâmicos C57BL , Fosfolipídeo Hidroperóxido Glutationa Peroxidase , Complicações Cognitivas Pós-Operatórias , Animais , Ferroptose/fisiologia , Ferroptose/efeitos dos fármacos , Fatores de Transcrição MEF2/metabolismo , Camundongos , Complicações Cognitivas Pós-Operatórias/metabolismo , Fosfolipídeo Hidroperóxido Glutationa Peroxidase/metabolismo , Fosfolipídeo Hidroperóxido Glutationa Peroxidase/genética , Masculino , Hipocampo/metabolismoRESUMO
In this editorial, we comment on the article by Zhou et al. The study reveals the connection between ferroptosis and pyroptosis and the effect of silent information regulator sirtuin 1 (SIRT1) activation in acute liver failure (ALF). ALF is characterized by a sudden and severe liver injury resulting in significant hepatocyte damage, often posing a high risk of mortality. The predominant form of hepatic cell death in ALF involves apoptosis, ferroptosis, autophagy, pyroptosis, and necroptosis. Glutathione peroxidase 4 (GPX4) inhibition sensitizes the cell to ferroptosis and triggers cell death, while Gasdermin D (GSDMD) is a mediator of pyroptosis. The study showed that ferroptosis and pyroptosis in ALF are regulated by blocking the p53/GPX4/GSDMD pathway, bridging the gap between the two processes. The inhibition of p53 elevates the levels of GPX4, reducing the levels of inflammatory and liver injury markers, ferroptotic events, and GSDMD-N protein levels. Reduced p53 expression and increased GPX4 on deletion of GSDMD indicated ferroptosis and pyroptosis interaction. SIRT1 is a NAD-dependent deacetylase, and its activation attenuates liver injury and inflammation, accompanied by reduced ferroptosis and pyroptosis-related proteins in ALF. SIRT1 activation also inhibits the p53/GPX4/GSDMD axis by inducing p53 acetylation, attenuating LPS/D-GalN-induced ALF.
Assuntos
Ferroptose , Peptídeos e Proteínas de Sinalização Intracelular , Falência Hepática Aguda , Proteínas de Ligação a Fosfato , Fosfolipídeo Hidroperóxido Glutationa Peroxidase , Sirtuína 1 , Proteína Supressora de Tumor p53 , Sirtuína 1/metabolismo , Sirtuína 1/genética , Falência Hepática Aguda/metabolismo , Falência Hepática Aguda/patologia , Proteína Supressora de Tumor p53/metabolismo , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/genética , Ferroptose/efeitos dos fármacos , Fosfolipídeo Hidroperóxido Glutationa Peroxidase/metabolismo , Fosfolipídeo Hidroperóxido Glutationa Peroxidase/genética , Animais , Proteínas de Ligação a Fosfato/metabolismo , Proteínas de Ligação a Fosfato/genética , Transdução de Sinais , Piroptose/efeitos dos fármacos , Hepatócitos/metabolismo , Fígado/patologia , Fígado/metabolismo , Camundongos , GasderminasRESUMO
In this editorial, we comment on the article by Zhou et al published in a recent issue. We specifically focus on the crucial roles of ferroptosis and pyroptosis in acute liver failure (ALF), a disease with high mortality rates. Ferroptosis is the result of increased intracellular reactive oxygen species due to iron accumulation, glutathione (GSH) depletion, and decreased GSH peroxidase 4 activity, while pyroptosis is a procedural cell death mediated by gasdermin D which initiates a sustained inflammatory process. In this review, we describe the characteristics of ferroptosis and pyroptosis, and discuss the involvement of the two cell death modes in the onset and development of ALF. Furthermore, we summarize several interfering methods from the perspective of ferroptosis and pyroptosis for the alleviation of ALF. These observations might provide new targets and a theoretical basis for the treatment of ALF, which are also crucial for improving the prognosis of patients with ALF.
Assuntos
Ferroptose , Falência Hepática Aguda , Piroptose , Espécies Reativas de Oxigênio , Humanos , Falência Hepática Aguda/patologia , Falência Hepática Aguda/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Ferro/metabolismo , Animais , Glutationa/metabolismo , Proteínas de Ligação a Fosfato/metabolismo , Fígado/patologia , Fígado/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Prognóstico , Fosfolipídeo Hidroperóxido Glutationa Peroxidase/metabolismo , GasderminasRESUMO
BACKGROUND: Myocardial ischemia-reperfusion injury (MI/RI) is an unavoidable risk event for acute myocardial infarction, with ferroptosis showing close involvement. We investigated the mechanism of MI/RI inducing myocardial injury by inhibiting the ferroptosis-related SLC7A11/glutathione (GSH)/glutathione peroxidase 4 (GPX4) pathway and activating mitophagy. METHODS: A rat MI/RI model was established, with myocardial infarction area and injury assessed by TTC and H&E staining. Rat cardiomyocytes H9C2 were cultured in vitro, followed by hypoxia/reoxygenation (H/R) modeling and the ferroptosis inhibitor lipoxstatin-1 (Lip-1) treatment, or 3-Methyladenine or rapamycin treatment and overexpression plasmid (oe-SLC7A11) transfection during modeling. Cell viability and death were evaluated by CCK-8 and LDH assays. Mitochondrial morphology was observed by transmission electron microscopy. Mitochondrial membrane potential was detected by fluorescence dye JC-1. Levels of inflammatory factors, reactive oxygen species (ROS), Fe2+, malondialdehyde, lipid peroxidation, GPX4 enzyme activity, glutathione reductase, GSH and glutathione disulfide, and SLC7A11, GPX4, LC3II/I and p62 proteins were determined by ELISA kit, related indicator detection kits and Western blot. RESULTS: The ferroptosis-related SLC7A11/GSH/GPX4 pathway was repressed in MI/RI rat myocardial tissues, inducing myocardial injury. H/R affected GSH synthesis and inhibited GPX4 enzyme activity by down-regulating SLC7A11, thus promoting ferroptosis in cardiomyocytes, which was averted by Lip-1. SLC7A11 overexpression improved H/R-induced cardiomyocyte ferroptosis via the GSH/GPX4 pathway. H/R activated mitophagy in cardiomyocytes. Mitophagy inhibition reversed H/R-induced cellular ferroptosis. Mitophagy activation partially averted SLC7A11 overexpression-improved H/R-induced cardiomyocyte ferroptosis. H/R suppressed the ferroptosis-related SLC7A11/GSH/GPX4 pathway by inducing mitophagy, leading to cardiomyocyte injury. CONCLUSIONS: Increased ROS under H/R conditions triggered cardiomyocyte injury by inducing mitophagy to suppress the ferroptosis-related SLC7A11/GSH/GPX4 signaling pathway activation.
Assuntos
Sistema y+ de Transporte de Aminoácidos , Modelos Animais de Doenças , Ferroptose , Glutationa , Mitofagia , Traumatismo por Reperfusão Miocárdica , Miócitos Cardíacos , Fosfolipídeo Hidroperóxido Glutationa Peroxidase , Ratos Sprague-Dawley , Transdução de Sinais , Ferroptose/efeitos dos fármacos , Animais , Traumatismo por Reperfusão Miocárdica/metabolismo , Traumatismo por Reperfusão Miocárdica/patologia , Traumatismo por Reperfusão Miocárdica/genética , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Fosfolipídeo Hidroperóxido Glutationa Peroxidase/metabolismo , Fosfolipídeo Hidroperóxido Glutationa Peroxidase/genética , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Miócitos Cardíacos/efeitos dos fármacos , Ratos , Glutationa/metabolismo , Masculino , Sistema y+ de Transporte de Aminoácidos/metabolismo , Sistema y+ de Transporte de Aminoácidos/genética , Linhagem Celular , Mitofagia/efeitos dos fármacos , Infarto do Miocárdio/patologia , Infarto do Miocárdio/metabolismo , Infarto do Miocárdio/genética , Mitocôndrias Cardíacas/metabolismo , Mitocôndrias Cardíacas/patologia , Mitocôndrias Cardíacas/efeitos dos fármacos , Estresse Oxidativo , Espécies Reativas de Oxigênio/metabolismoRESUMO
Ferroptosis is an important pathological mechanism of chronic heart failure (CHF). This study aimed to investigate the protective mechanism of Astragaloside IV (AS-IV) on CHF rats by integrating bioinformatics and ferroptosis. CHF-related targets and ferroptosis-related targets were collected. After the intersection, the common targets were obtained. The PPI network of the common targets was constructed, and topological analysis of the network was carried out. The target with the highest topological parameter values was selected as the key target. The key target p53 was obtained through bioinformatics analysis, and its molecular docking model with AS-IV was obtained, as well as molecular dynamics simulation analysis. The rat models of CHF after myocardial infarction were established by ligation of left coronary artery and treated with AS-IV for 4 weeks. AS-IV treatment significantly improved cardiac function in CHF rats, improved cardiomyocyte morphology and myocardial fibrosis, reduced mitochondrial damage, decreased myocardial MDA and Fe2+ content, increased GSH content, inhibited the expression of p53 and p-p53, and up-regulated the expression of SLC7A11 and GPX4. In conclusion, AS-IV improved cardiac function in CHF rats, presumably by regulating p53/SLC7A11/GPX4 signaling pathway and inhibiting myocardial ferroptosis.
Assuntos
Biologia Computacional , Ferroptose , Insuficiência Cardíaca , Saponinas , Triterpenos , Animais , Ferroptose/efeitos dos fármacos , Triterpenos/farmacologia , Saponinas/farmacologia , Insuficiência Cardíaca/tratamento farmacológico , Insuficiência Cardíaca/metabolismo , Ratos , Biologia Computacional/métodos , Masculino , Fosfolipídeo Hidroperóxido Glutationa Peroxidase/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Simulação de Acoplamento Molecular , Doença Crônica , Modelos Animais de Doenças , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/patologia , Infarto do Miocárdio/tratamento farmacológico , Infarto do Miocárdio/metabolismo , Infarto do Miocárdio/patologia , Simulação de Dinâmica Molecular , Miocárdio/metabolismo , Miocárdio/patologiaRESUMO
Rationale: COPD patients are largely asymptomatic until the late stages when prognosis is generally poor. In this study, we shifted the focus to pre-COPD and smoking stages, and found enrichment of hypoxia inducible factor (HIF)-3α is in pre-COPD samples. Smoking induced regional tissue hypoxia and emphysema have been found in COPD patients. However, the mechanisms underlying hypoxia especially HIF-3α and COPD have not been investigated. Methods: We performed bulk-RNA sequencing on 36 peripheral lung tissue specimens from non-smokers, smokers, pre-COPD and COPD patients, and using "Mfuzz" algorithm to analysis the dataset dynamically. GSE171541 and EpCAM co-localization analyses were used to explore HIF-3α localization. Further, SftpcCreert2/+R26LSL-Hif3a knock-in mice and small molecular inhibitors in vitro were used to explore the involvement of HIF-3α in the pathophysiology of COPD. Results: Reactive oxygen species (ROS) and hypoxia were enriched in pre-COPD samples, and HIF-3α was downregulated in alveolar epithelial cells in COPD. In vitro experiments using lentivirus transfection, bulk-RNA seq, and RSL3 showed that the activation of the HIF-3α-GPx4 axis inhibited alveolar epithelial cell ferroptosis when treated with cigarettes smoking extracts (CSE). Further results from SftpcCreert2/+R26LSL-Hif3a knock-in mice demonstrated overexpression of HIF-3α inhibited alveolar epithelial cells ferroptosis and prevented the decline of lung function. Conclusion: Hypoxia and oxidation-related damage begins years before the onset of COPD symptoms, suggesting the imbalance and impairment of intracellular homeostatic system. The activation of the HIF-3α-GPx4 axis is a promising treatment target. By leveraging this comprehensive analysis method, more potential targets could be found and enhancing our understanding of the pathogenesis.
Assuntos
Células Epiteliais Alveolares , Fatores de Transcrição Hélice-Alça-Hélice Básicos , Ferroptose , Fosfolipídeo Hidroperóxido Glutationa Peroxidase , Doença Pulmonar Obstrutiva Crônica , Doença Pulmonar Obstrutiva Crônica/metabolismo , Doença Pulmonar Obstrutiva Crônica/patologia , Ferroptose/efeitos dos fármacos , Animais , Humanos , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Camundongos , Células Epiteliais Alveolares/metabolismo , Fosfolipídeo Hidroperóxido Glutationa Peroxidase/metabolismo , Fosfolipídeo Hidroperóxido Glutationa Peroxidase/genética , Espécies Reativas de Oxigênio/metabolismo , Masculino , Feminino , Fumar/efeitos adversos , Pessoa de Meia-Idade , Camundongos Endogâmicos C57BL , Proteínas Repressoras , Proteínas Reguladoras de ApoptoseRESUMO
Enhancement of Connexin43 (Cx43) and ferroptosis are respectively associated with the exacerbation of myocardial ischemia-reperfusion injury (MIRI) in diabetes. Myocardial vulnerability to ischemic insult has been shown to vary during early and later phases of diabetes in experimental settings. Whether or not Connexin43 (Cx43) and ferroptosis interplay during MIRI in diabetes is unknown. We, thus, aimed to investigate whether or not the content of myocardial Cx43 may be attributable to myocardial vulnerability to MIRI at different stages of diabetes and also to explore the potential interplay between Cx43 and ferroptosis in this pathology. Age-matched control and subgroups of Streptozotocin-induced diabetic mice were subjected to MIRI induced by 30 minutes coronary artery occlusion and 2 hours reperfusion respectively at 1, 2 and 5 weeks of diabetes. Rat cardiac H9C2 cells were exposed to high glucose (HG) for 48h in the absence or presence of Cx43 gene knockdown followed by hypoxia/reoxygenation (HR) respectively for 6 and 12 hours. Post-ischemic myocardial infarct size was reduced in 1 and 2 weeks DM mice concomitant with enhanced GPX4 and reduced cardiac Cx43 and ferroptosis as compared to control. By contrast, cardiac GPX4 was significantly reduced while Cx43 increased at DM 5 weeks (D5w) which was correspondent to significant increases in ferroptosis and myocardial infarction. Post-ischemic cardiac function was improved in 1 and 2 weeks but worsened in 5w DM mice as compared with non-diabetic control. GAP19 (Cx43 inhibitor) significantly attenuated ferroptosis and reduced myocardial infarction in D5w mice. Erastin (ferroptosis activator) reversed the cardioprotective effect of GAP19. In vitro, HR significantly reduced cell viability accompanied with reduced GPX4 but elevated Cx43 expression, MDA production and ferroptosis. Cx43 gene knockdown in H9C2 resulted in a significant increase in GPX4, reduction in MDA and ferroptosis, and subsequently reduced post-hypoxic cell viability. The beneficial effects of Cx43 gene knock-down was minified or eliminated by Erastin. It is concluded that Cx43 overexpression exacerbates MIRI under diabetic conditions via promoting ferroptosis, while its down-regulation at early state of diabetes is attributable to enhanced myocardial tolerance to MIRI.
Assuntos
Conexina 43 , Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 1 , Ferroptose , Traumatismo por Reperfusão Miocárdica , Fosfolipídeo Hidroperóxido Glutationa Peroxidase , Animais , Ferroptose/genética , Conexina 43/metabolismo , Conexina 43/genética , Camundongos , Traumatismo por Reperfusão Miocárdica/metabolismo , Traumatismo por Reperfusão Miocárdica/patologia , Traumatismo por Reperfusão Miocárdica/genética , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/patologia , Ratos , Fosfolipídeo Hidroperóxido Glutationa Peroxidase/metabolismo , Fosfolipídeo Hidroperóxido Glutationa Peroxidase/genética , Diabetes Mellitus Tipo 1/complicações , Diabetes Mellitus Tipo 1/patologia , Diabetes Mellitus Tipo 1/metabolismo , Diabetes Mellitus Tipo 1/genética , Masculino , Técnicas de Silenciamento de Genes , Humanos , Linhagem Celular , Miocárdio/patologia , Miocárdio/metabolismo , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Infarto do Miocárdio/patologia , Infarto do Miocárdio/genética , Infarto do Miocárdio/metabolismoRESUMO
Hemolysis drives susceptibility to lung injury and predicts poor outcomes in diseases, such as malaria and sickle cell disease (SCD). However, the underlying pathological mechanism remains elusive. Here, we report that major facilitator superfamily domain containing 7 C (MFSD7C) protects the lung from hemolytic-induced damage by preventing ferroptosis. Mechanistically, MFSD7C deficiency in HuLEC-5A cells leads to mitochondrial dysfunction, lipid remodeling and dysregulation of ACSL4 and GPX4, thereby enhancing lipid peroxidation and promoting ferroptosis. Furthermore, systemic administration of MFSD7C mRNA-loaded nanoparticles effectively prevents lung injury in hemolytic mice, such as HbSS-Townes mice and PHZ-challenged 7 C-/- mice. These findings present the detailed link between hemolytic complications and ferroptosis, providing potential therapeutic targets for patients with hemolytic disorders.
Assuntos
Ferroptose , Hemólise , Camundongos Knockout , Fosfolipídeo Hidroperóxido Glutationa Peroxidase , Animais , Feminino , Humanos , Masculino , Camundongos , Anemia Falciforme/complicações , Anemia Falciforme/genética , Coenzima A Ligases/metabolismo , Coenzima A Ligases/genética , Modelos Animais de Doenças , Ferroptose/efeitos dos fármacos , Ferroptose/genética , Hemólise/efeitos dos fármacos , Peroxidação de Lipídeos/efeitos dos fármacos , Pulmão/patologia , Pulmão/metabolismo , Lesão Pulmonar/metabolismo , Lesão Pulmonar/patologia , Lesão Pulmonar/prevenção & controle , Lesão Pulmonar/genética , Camundongos Endogâmicos C57BL , Mitocôndrias/metabolismo , Mitocôndrias/efeitos dos fármacos , Nanopartículas/química , Fosfolipídeo Hidroperóxido Glutationa Peroxidase/metabolismo , Fosfolipídeo Hidroperóxido Glutationa Peroxidase/genéticaRESUMO
Susceptibility of human cells to cold stress restricts the use of therapeutic hypothermia and long-term preservation of organs at low temperatures. In contrast, cells of mammalian hibernators possess remarkable cold resistance, but little is known about the molecular mechanisms underlying this phenomenon. In this study, we conducted a gain-of-function screening of genes that confer cold resistance to cold-vulnerable human cells using a cDNA library constructed from the Syrian hamster, a mammalian hibernator, and identified Gpx4 as a potent suppressor of cold-induced cell death. Additionally, genetic deletion of or pharmacological inhibition of Gpx4 revealed that Gpx4 is necessary for suppressing lipid peroxidation specifically under cold in hamster cell lines. Genetic disruption of other ferroptosis-suppressing pathways, namely biopterin synthesis and mitochondrial or plasma membrane CoQ reduction pathways, also accelerated cold-induced cell death under Gpx4 dysfunction. Collectively, ferroptosis-suppressing pathways protect the cells of a mammalian hibernator from cold-induced cell death and the augmentation of these pathways renders cold resistance to cells of non-hibernators, including humans.
Assuntos
Temperatura Baixa , Hibernação , Peroxidação de Lipídeos , Fosfolipídeo Hidroperóxido Glutationa Peroxidase , Animais , Humanos , Hibernação/genética , Fosfolipídeo Hidroperóxido Glutationa Peroxidase/metabolismo , Fosfolipídeo Hidroperóxido Glutationa Peroxidase/genética , Ferroptose/genética , Cricetinae , Mitocôndrias/metabolismo , Mitocôndrias/genética , Mesocricetus , Morte Celular , Ubiquinona/análogos & derivados , Ubiquinona/metabolismo , Ubiquinona/farmacologia , Linhagem CelularRESUMO
This study aims to investigate the mechanism of ferroptosis mediated by the nuclear factor-E2-related factor 2(Nrf2)/solute carrier family 7 member 11(SLC7A11, also known as xCT)/glutathione peroxidase 4(GPX4) signaling pathway in radiationinduced pulmonary fibrosis and the intervention effect of Angelicae Sinensis Radix(ASR) and Astragali Radix(AR) ultrafiltration extract. Fifty Wistar rats were randomly divided into five groups, with 10 rats in each group. Except for the blank group without radiation, the rats in each group were anesthetized and subjected to a single local chest irradiation of 40 Gy X-rays once to establish a rat model of radiation-induced pulmonary fibrosis. After radiation, the rats in the intervention groups were orally administered with ASR-AR ultrafiltration extract at doses of 0. 12, 0. 24, and 0. 48 g·kg~(-1), respectively, once a day for 30 days. After 30 days of continuous administration, the levels of oxidative stress indicators superoxide dismutase(SOD) activity, reduced glutathione(GSH),malondialdehyde(MDA), and ferrous ion(Fe~(2+)) in lung tissues of each group were detected by colorimetry. Immunofluorescence was used to detect reactive oxygen species(ROS) fluorescence expression in lung tissues. Hematoxylin-eosin(HE) and Masson staining were performed to observe pathological changes in lung tissues. Immunohistochemistry and Western blot were used to detect the expression levels of Nrf2/xCT/GPX4 signaling pathway and fibrotic proteins in lung tissues. The results showed that compared with the results in the blank group, the levels of Fe~(2+) and MDA in the model group increased, while SOD activity and GSH levels decreased,and ROS levels increased. HE and Masson staining results showed that the structure of lung tissue was seriously damaged, the pulmonary interstitium was significantly proliferated, the alveoli collapsed and consolidated severely, and there were more inflammatory cell aggregates and collagen fiber deposits. Transmission electron microscopy showed that the degree of lung tissue damage in the model group was relatively high, with increased, smaller, and disorganized damaged mitochondria, irregular morphology, shallow matrix,most mitochondria ruptured and shortened, mildly expanded, some mitochondria with increased electron density of the matrix, partial mitochondrial outer membrane rupture, and characteristic changes of ferroptosis-specific mitochondria. Immunohistochemistry showed that the expression of transferrin receptor protein 1(TFR1) in lung tissues was significantly increased, while the expression of GPX4,ferritin heavy chain 1(FTH1), Nrf2, and xCT was significantly decreased. Western blot showed that the expression of α-smooth muscle actin(α-SMA) and collagen â protein increased. Compared with the model group, the intervention group with ASR-AR ultrafiltration extract significantly improved lipid peroxidation and antioxidant-related indicators, decreased Fe~(2+) levels, alleviated fibrosis, and decreased the expression of TFR1, α-SMA, and collagen â proteins in lung tissues, while increased the expression of GPX4, FTH1, Nrf2, and xCT proteins. In summary, ASR-AR ultrafiltration extract has an ameliorative effect on radiation-induced pulmonary fibrosis, and its mechanism may involve the inhibition of ferroptosis by regulating the Nrf2/xCT/GPX4 signaling pathway.
Assuntos
Angelica sinensis , Medicamentos de Ervas Chinesas , Ferroptose , Fator 2 Relacionado a NF-E2 , Fosfolipídeo Hidroperóxido Glutationa Peroxidase , Fibrose Pulmonar , Ratos Wistar , Transdução de Sinais , Animais , Ratos , Ferroptose/efeitos dos fármacos , Fator 2 Relacionado a NF-E2/metabolismo , Fator 2 Relacionado a NF-E2/genética , Fibrose Pulmonar/metabolismo , Fibrose Pulmonar/tratamento farmacológico , Transdução de Sinais/efeitos dos fármacos , Fosfolipídeo Hidroperóxido Glutationa Peroxidase/metabolismo , Fosfolipídeo Hidroperóxido Glutationa Peroxidase/genética , Masculino , Medicamentos de Ervas Chinesas/farmacologia , Medicamentos de Ervas Chinesas/administração & dosagem , Angelica sinensis/química , Astragalus propinquus/química , Astrágalo/química , Estresse Oxidativo/efeitos dos fármacosRESUMO
BACKGROUND: Ferroptosis is an important type of cell death contributing to myocardial dysfunction induced by whole body ischemia reperfusion following cardiac arrest (CA) and resuscitation. Sulforaphane (SFN), known as the activator of the nuclear factor E2-related factor 2 (Nrf2), has been proven to effectively alleviate regional myocardial ischemia reperfusion injury. The present study was designed to investigate whether SFN could improve post-resuscitation myocardial dysfunction by inhibiting cardiomyocytes ferroptosis and its potential regulatory mechanism. METHODS AND RESULTS: An in vivo pig model of CA and resuscitation was established. Hypoxia/reoxygenation (H/R)-stimulated AC16 cardiomyocytes was constructed as an in vitro model to simulate the process of CA and resuscitation. In vitro experiment, SFN reduced ferroptosis-related ferrous iron, lipid reactive oxygen species, and malondialdehyde, increased glutathione, and further promoted cell survival after H/R stimulation in AC16 cardiomyocytes. Mechanistically, the activation of Nrf2 with the SFN decreased interferon regulatory factor 1 (IRF1) expression, then reduced its binding to the promoter of glutathione peroxidase 4 (GPX4), and finally recovered the latter's transcription after H/R stimulation in AC16 cardiomyocytes. In vivo experiment, SFN reversed abnormal expression of IRF1 and GPX4, inhibited cardiac ferroptosis, and improved myocardial dysfunction after CA and resuscitation in pigs. CONCLUSIONS: SFN could effectively improve myocardial dysfunction after CA and resuscitation, in which the mechanism was potentially related to the inhibition of cardiomyocytes ferroptosis through the regulation of Nrf2/IRF1/GPX4 pathway.
Assuntos
Ferroptose , Fator Regulador 1 de Interferon , Isotiocianatos , Miócitos Cardíacos , Fator 2 Relacionado a NF-E2 , Fosfolipídeo Hidroperóxido Glutationa Peroxidase , Transdução de Sinais , Sulfóxidos , Animais , Ferroptose/efeitos dos fármacos , Isotiocianatos/farmacologia , Fator 2 Relacionado a NF-E2/metabolismo , Sulfóxidos/farmacologia , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Suínos , Fosfolipídeo Hidroperóxido Glutationa Peroxidase/metabolismo , Fator Regulador 1 de Interferon/metabolismo , Fator Regulador 1 de Interferon/genética , Transdução de Sinais/efeitos dos fármacos , Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , Traumatismo por Reperfusão Miocárdica/metabolismo , Traumatismo por Reperfusão Miocárdica/patologia , Linhagem Celular , Parada Cardíaca/tratamento farmacológico , Masculino , Modelos Animais de DoençasRESUMO
Function of HECTD2 in renal cell carcinoma malignant progression is undefined. Molecular mechanism behind anti-cancer effects of veratric acid (VA) from traditional Chinese medicine (TCM) is underexplored. The Cancer Genome Atlas was leveraged to study HECTD2 expression in renal cell carcinoma and its relationship with histological grading. Kaplan-Meier survival analysis was performed. HECTD2 expression was detected in cancer cells and tissues via qRT-PCR and immunohistochemistry. GPX4 and SLC7A11 expression in tumor samples with high or low HECTD2 expression was examined by immunohistochemistry, cell viability by CCK8, cell proliferation by colony formation assay, lipid ROS and mitochondrial superoxide levels by flow cytometry, Fe2+ and MDA content by assay kits, and GPX4 and SLC7A11 proteins by western blot. SeeSAR software screened TCM small molecule compounds with highest affinity to HECTD2, confirmed with cellular thermal shift assay. VA IC50 was measured by CCK8. Xenograft model was developed and treated with VA. Tumor size and weight were monitored, with immunohistochemistry to detect HECTD2 expression in tumors and assess ferroptosis-related markers. HECTD2 was overexpressed in tumor tissues and cells, which positively correlated with histological grading. HECTD2 depletion inhibited cell vitality and proliferation, raised intracellular lipid ROS, mitochondrial superoxide, Fe2+, and MDA. HECTD2 was a target with highest VA affinity. In vitro and vivo experiments concurred that VA treatment hindered malignancy of renal cell carcinoma and enhanced its susceptibility to ferroptosis. HECTD2 supports ferroptosis resistance in renal cell carcinoma, but VA, through its targeting of HECTD2, initiates ferroptosis, showcasing its anti-cancer efficacy.
Assuntos
Carcinoma de Células Renais , Ferroptose , Neoplasias Renais , Ferroptose/efeitos dos fármacos , Carcinoma de Células Renais/metabolismo , Carcinoma de Células Renais/tratamento farmacológico , Carcinoma de Células Renais/patologia , Carcinoma de Células Renais/genética , Humanos , Neoplasias Renais/metabolismo , Neoplasias Renais/patologia , Neoplasias Renais/tratamento farmacológico , Neoplasias Renais/genética , Animais , Camundongos , Proliferação de Células/efeitos dos fármacos , Linhagem Celular Tumoral , Fosfolipídeo Hidroperóxido Glutationa Peroxidase/metabolismo , Fosfolipídeo Hidroperóxido Glutationa Peroxidase/genética , Camundongos Nus , Ensaios Antitumorais Modelo de Xenoenxerto , Sistema y+ de Transporte de Aminoácidos/metabolismo , Sistema y+ de Transporte de Aminoácidos/genética , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , MasculinoRESUMO
Drug resistance is a critical impediment to efficient therapy of diffuse large B-cell lymphoma (DLBCL) patients. Recent studies have highlighted the association between ferroptosis and drug resistance that has been reported. Fatty acid synthase (FASN) is always related to a poor prognosis. In this study, we investigate the impact of FASN on drug resistance in DLBCL and explore its potential modulation of ferroptosis mechanisms. The clinical correlation of FASN mRNA expression was first analyzed to confirm the role of FASN on drug resistance in DLBCL based on the TCGA database. Next, the impact of FASN on ferroptosis was investigated in vitro and in vivo. Furthermore, a combination of RNA-seq, western blot, luciferase reporter, and ChIP experiments was employed to elucidate the underlying mechanism. The prognosis for patients with DLBCL was worse when FASN was highly expressed, particularly in those undergoing chemotherapy for Adriamycin (ADM). FASN promoted tumor growth and resistance of DLBCL to ADM, both in vitro and in vivo. It is noteworthy that this effect was achieved by inhibiting ferroptosis, since Fer-1 (a ferroptosis inhibitor) treatment significantly recovered the effects of silencing FASN on inhibiting ferroptosis, while Erastin (a ferroptosis inducer) treatment attenuated the impact of overexpressing FASN. Mechanistically, FASN activated NF-κB/STAT3 signaling pathway through phosphorylating the upstream IKKα and IκBα, and the activated STAT3 promoted GPX4 expression by directly binding to GPX4 promoter. FASN inhibits ferroptosis in DLBCL via NF-κB/STAT3/GPX4 signaling pathway, indicating its critical role in mediating ADM resistance of DLBCL.
Assuntos
Doxorrubicina , Resistencia a Medicamentos Antineoplásicos , Ácido Graxo Sintase Tipo I , Ferroptose , Linfoma Difuso de Grandes Células B , NF-kappa B , Fosfolipídeo Hidroperóxido Glutationa Peroxidase , Fator de Transcrição STAT3 , Humanos , Ferroptose/efeitos dos fármacos , Ferroptose/genética , Linfoma Difuso de Grandes Células B/genética , Linfoma Difuso de Grandes Células B/metabolismo , Linfoma Difuso de Grandes Células B/patologia , Linfoma Difuso de Grandes Células B/tratamento farmacológico , NF-kappa B/metabolismo , Camundongos , Animais , Fosfolipídeo Hidroperóxido Glutationa Peroxidase/metabolismo , Fosfolipídeo Hidroperóxido Glutationa Peroxidase/genética , Resistencia a Medicamentos Antineoplásicos/genética , Doxorrubicina/farmacologia , Doxorrubicina/uso terapêutico , Ácido Graxo Sintase Tipo I/metabolismo , Ácido Graxo Sintase Tipo I/genética , Fator de Transcrição STAT3/metabolismo , Linhagem Celular Tumoral , Ensaios Antitumorais Modelo de Xenoenxerto , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Feminino , Masculino , Transdução de Sinais/efeitos dos fármacos , Camundongos Nus , PrognósticoRESUMO
OBJECTIVE: To investigate the effect of sanguinarine (SAN) on proliferation and ferroptosis of colorectal cancer cells. METHODS: SW620 and HCT-116 cells treated with different concentrations of SAN were examined for cell viability changes using CCK8 assay to determine the IC50 of SAN in the two cells. The inhibitory effects of SAN on proliferation, invasion and migration of the cells were evaluated using colony-forming assay and Transwell assays. ROS production in the treated cells was analyzed with flow cytometry, and lipid peroxide production was assessed by detecting malondialdehyde (MDA) level. Glutathione (GSH) levels in the cells were detected, and Western blotting was used to detect the expressions of ferroptosis-related proteins STUB1 and GPX4. RESULTS: SAN significantly inhibited the proliferation, invasion and migration of SW620 and HCT-116 cells. SAN treatment significantly promoted ROS production, increased intracellular MDA level, and lowered GSH level in the two cells (P<0.05). Western blotting showed that SAN significantly upregulated the expression of STUB1 and down-regulated the expression of its downstream protein GPX4 (P<0.05). CONCLUSION: SAN induces ferroptosis in colorectal cancer cells by regulating STUB1/GPX4, which may serve as a new therapeutic target for colorectal cancer.
Assuntos
Benzofenantridinas , Proliferação de Células , Neoplasias Colorretais , Ferroptose , Isoquinolinas , Fosfolipídeo Hidroperóxido Glutationa Peroxidase , Humanos , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Neoplasias Colorretais/genética , Ferroptose/efeitos dos fármacos , Fosfolipídeo Hidroperóxido Glutationa Peroxidase/metabolismo , Proliferação de Células/efeitos dos fármacos , Isoquinolinas/farmacologia , Linhagem Celular Tumoral , Benzofenantridinas/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Regulação para Baixo , Células HCT116 , Regulação para Cima/efeitos dos fármacos , Movimento Celular/efeitos dos fármacosRESUMO
Cis-dichlorodiammineplatinum(II) (CDDP), while widely utilized in tumor therapy, results in toxic side effects that patients find intolerable. The specific mechanism by which CDDP inflicts ovarian damage remains unclear. This study aimed to explore the involvement of ferrostatin-1 (FER-1) and ferroptosis in CDDP-induced ovarian toxicity. This study established models of CDDP-induced injury in granulosa cells (GCs) and rat model of premature ovarian failure (POF). CCK-8 assessed the effects of CDDP and FER-1 on GC viability. FerroOrange and Mito-FerroGreen, DCFH-DA and MitoSox-Red, Rhodamine 123 and Transmission electron microscopy (TEM) measured Fe2+, reactive oxygen species (ROS), mitochondrial membrane potential and the mitochondrial morphology in GC cells, respectively. Serum hormone levels; organ indices; malondialdehyde, superoxide dismutase, and glutathione analyses; and western blotting were performed to examine ferroptosis's role in vitro. Molecular docking simulation was evaluated the interaction between FER-1 and GPX4 or FER-1 and NRF2. Molecular docking simulations were conducted to evaluate the interactions between FER-1 and GPX4, as well as FER-1 and NRF2. The findings revealed that CDDP-induced ovarian toxicity involved iron accumulation, increased ROS accumulation, and mitochondrial dysfunction, leading to endocrine disruption and tissue damage in rats. These changes correlated with NRF2, HO-1, and GPX4 levels. However, FER-1 decreased the extent of ferroptosis. Thus, ferroptosis appears to be a crucial mechanism of CDDP-induced ovarian injury, with GPX4 as potential protective targets.
Assuntos
Cisplatino , Cicloexilaminas , Ferroptose , Simulação de Acoplamento Molecular , Fenilenodiaminas , Espécies Reativas de Oxigênio , Animais , Feminino , Ferroptose/efeitos dos fármacos , Cicloexilaminas/farmacologia , Ratos , Espécies Reativas de Oxigênio/metabolismo , Cisplatino/efeitos adversos , Fenilenodiaminas/farmacologia , Células da Granulosa/efeitos dos fármacos , Células da Granulosa/metabolismo , Ovário/efeitos dos fármacos , Ovário/metabolismo , Ovário/patologia , Insuficiência Ovariana Primária/induzido quimicamente , Insuficiência Ovariana Primária/metabolismo , Fosfolipídeo Hidroperóxido Glutationa Peroxidase/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Ratos Sprague-Dawley , Modelos Animais de Doenças , Humanos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismoRESUMO
BACKGROUND: Ferroptosis, a novel iron-ion-dependent metabolic cell death mode with lipid peroxides as the main driving substrate, plays an irreplaceable role in the development and preventive treatment of hepatocellular carcinoma. Curcumin has potent pharmacological anti-tumor effects. AIM OF THE STUDY: We aimed to evaluate the ex vivo and in vivo cancer inhibitory activity of curcumin and its specific mechanism of action. MATERIALS AND METHODS: We used the hepatocellular carcinoma cell lines HepG2 and SMMC7721 to assess the direct inhibition of hepatocellular carcinoma proliferation by curcumin in vitro and a tumor xenograft model to evaluate the in vivo cancer inhibitory effect of curcumin. RESULTS: In this study, we found that ferroptosis's inhibitors specifically reversed the curcumin-induced cell death pattern in HCC. After curcumin intervention, there was a substantial increase in MDA levels and iron ion levels, and a decrease in intracellular GSH levels. Meanwhile, the expression of GPX4 and SLC7A11 was significantly reduced at the protein levels, while ACSL4 and PTGS2 expression was significantly increased. CONCLUSIONS: This study showed that curcumin significantly decreased the proliferation of HCC cells and significantly increased the sensitivity of ferroptosis. These results suggest that ACSL4 is a viable target for curcumin-induced ferroptosis in treating HCC.
Assuntos
Carcinoma Hepatocelular , Proliferação de Células , Coenzima A Ligases , Curcumina , Ferroptose , Neoplasias Hepáticas , Regulação para Cima , Ensaios Antitumorais Modelo de Xenoenxerto , Ferroptose/efeitos dos fármacos , Curcumina/farmacologia , Humanos , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/metabolismo , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/metabolismo , Animais , Camundongos , Coenzima A Ligases/metabolismo , Regulação para Cima/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Fosfolipídeo Hidroperóxido Glutationa Peroxidase/metabolismo , Camundongos Nus , Sistema y+ de Transporte de Aminoácidos/metabolismo , Sistema y+ de Transporte de Aminoácidos/genética , Células Hep G2 , Linhagem Celular Tumoral , Camundongos Endogâmicos BALB C , Masculino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacosRESUMO
BRCA1 is one of the most frequently-mutated tumor suppressor genes in ovarian and breast cancers. Loss of BRCA1 triggers homologous recombination (HR) repair deficiency, consequently leading to genomic instability and PARP inhibitors (PARPi)-associated synthetic lethality. Although, the roles of BRCA1 in DNA repair and replication have been extensively investigated, its tumor suppressive functions beyond genome safeguard remain poorly understood. Here, we report that BRCA1 promotes ferroptosis susceptibility through catalyzing K6-linked polyubiquitination of GPX4 and subsequently accelerating GPX4 degradation. Depletion of BRCA1 induces ferroptosis resistance in ovarian cancer cells due to elevated GPX4 protein, and silence of GPX4 significantly suppresses the growth of BRCA1-deficient ovarian cancer xenografts. Importantly, we found that PARPi triggers ferroptosis in ovarian cancer cells, inhibition of GPX4 markedly increase PARPi-induced ferroptosis in BRCA1-deficient ovarian cancer cells. Combined treatment of GPX4 inhibitor and PARPi produces synergistic anti-tumor efficacy in BRCA1-deficient ovarian cancer cells, patient derived organoid (PDO) and xenografts. Thus, our study uncovers a novel mechanism via which BRCA1 exerts tumor suppressive function through regulating ferroptosis, and demonstrates the potential of GPX4 as a therapeutic target for BRCA1-mutant cancers.
Assuntos
Proteína BRCA1 , Ferroptose , Neoplasias Ovarianas , Fosfolipídeo Hidroperóxido Glutationa Peroxidase , Inibidores de Poli(ADP-Ribose) Polimerases , Humanos , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Ferroptose/efeitos dos fármacos , Ferroptose/genética , Fosfolipídeo Hidroperóxido Glutationa Peroxidase/metabolismo , Fosfolipídeo Hidroperóxido Glutationa Peroxidase/genética , Feminino , Proteína BRCA1/genética , Proteína BRCA1/deficiência , Animais , Camundongos , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/patologia , Linhagem Celular Tumoral , Ensaios Antitumorais Modelo de Xenoenxerto , Ubiquitinação/efeitos dos fármacosRESUMO
Ferroptosis, a key factor in tumor progression, is poorly understood at the molecular level. This study investigates how ELK4 and CHMP6 regulate skin cutaneous melanoma (SKCM) cell proliferation and ferroptosis. Analysis of TCGA data reveals high expression of ELK4 and CHMP6 in SKCM. Overexpression of ELK4 or CHMP6 enhances cell proliferation, invasion, and migration while reducing ROS and Fe2 + levels. It also increases GPX4 and xCT expression and decreases ACSL4 levels in SKCM cells. The opposite effects are observed with ELK4 or CHMP6 knockdown. ELK4 binds to the CHMP6 promoter, promoting CHMP6 transcription. Knockdown of CHMP6 reverses the oncogenic effects of ELK4 overexpression. In conclusion, ELK4 enhances proliferation, invasion, and migration while inhibiting ferroptosis in SKCM cells by upregulating CHMP6 transcription. This study sheds light on the intricate mechanisms involved in SKCM progression and identifies potential therapeutic targets in melanoma treatment.
Assuntos
Movimento Celular , Proliferação de Células , Ferroptose , Regulação Neoplásica da Expressão Gênica , Melanoma , Neoplasias Cutâneas , Humanos , Sistema y+ de Transporte de Aminoácidos/metabolismo , Sistema y+ de Transporte de Aminoácidos/genética , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Coenzima A Ligases/metabolismo , Coenzima A Ligases/genética , Ferroptose/genética , Melanoma/patologia , Melanoma/genética , Melanoma/metabolismo , Melanoma Maligno Cutâneo , Invasividade Neoplásica/genética , Fosfolipídeo Hidroperóxido Glutationa Peroxidase/metabolismo , Fosfolipídeo Hidroperóxido Glutationa Peroxidase/genética , Neoplasias Cutâneas/patologia , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/metabolismoRESUMO
Polycystic ovary syndrome (PCOS) is associated with impaired adipose tissue physiology. Elevated brown adipose tissue (BAT) mass or activity has shown potential in the treatment of PCOS. In this study, we aimed to investigate whether BAT-derived exosomes (BAT-Exos), as potential biomarkers of BAT activity, exert similar benefits as BAT in the treatment of PCOS. PCOS was induced in female C57BL/6J mice orally administered 1 mg/kg of letrozole for 21 days. Subsequently, the animals underwent transplantation with BAT or administered BAT-Exos (200 µg) isolated from young healthy mice via the tail vein; healthy female mice were used as controls. The results indicate that BAT-Exos treatment significantly reduced body weight and improved insulin resistance in PCOS mice. In addition, BAT-Exos improved ovulation function by reversing the acyclicity of the estrous cycle, decreasing circulating luteinizing hormone and testosterone, recovering ovarian performance, and improving oocyte quality, leading to a higher pregnancy rate and litter size. Furthermore, western blotting revealed reduced expression of signal transducer and activator of transcription 3 (STAT3) and increased expression of glutathione peroxidase 4 (GPX4) in the ovaries of mice in the BAT-Exos group. To further explore the role of the STAT3/GPX4 signaling pathway in PCOS mice, we treated the mice with an intraperitoneal injection of 5 mg/kg stattic, a STAT3 inhibitor. Consistent with BAT-Exos treatment, the administration of stattic rescued letrozole-induced PCOS phenotypes. These findings suggest that BAT-Exos treatment might be a potential therapeutic strategy for PCOS and that the STAT3/GPX4 signaling pathway is a critical therapeutic target for PCOS.
Assuntos
Tecido Adiposo Marrom , Exossomos , Camundongos Endogâmicos C57BL , Fosfolipídeo Hidroperóxido Glutationa Peroxidase , Síndrome do Ovário Policístico , Fator de Transcrição STAT3 , Transdução de Sinais , Animais , Feminino , Camundongos , Tecido Adiposo Marrom/metabolismo , Exossomos/metabolismo , Resistência à Insulina , Letrozol/farmacologia , Ovário/metabolismo , Fosfolipídeo Hidroperóxido Glutationa Peroxidase/metabolismo , Síndrome do Ovário Policístico/metabolismo , Síndrome do Ovário Policístico/terapia , Fator de Transcrição STAT3/metabolismoRESUMO
The refractory luminal androgen receptor (LAR) subtype of triple-negative breast cancer (TNBC) patients is challenged by significant resistance to neoadjuvant chemotherapy and increased immunosuppression. Regarding the distinct upregulation of glutathione (GSH) and glutathione peroxidase 4 (GPX4) in LAR TNBC tumors, we herein designed a GSH-depleting phospholipid derivative (BPP) and propose a BPP-based nanotherapeutics of RSL-3 (GDNS), aiming to deplete intracellular GSH and repress GPX4 activity, thereby potentiating ferroptosis for treating LAR-subtype TNBC. GDNS treatment drastically downregulated the expression of GSH and GPX4, resulting in a 33.88-fold enhancement of lipid peroxidation and significant relief of immunosuppression in the 4T1 TNBC model. Moreover, GDNS and its combination with antibody against programed cell death protein 1 (antiPD-1) retarded tumor growth and produced 2.83-fold prolongation of survival in the LAR-positive TNBC model. Therefore, the GSH-disrupting GDNS represents an encouraging strategy to potentiate ferroptosis for treating refractory LAR-subtype TNBC.