Form Of Non-apoptotic Cell Death Research Articles

Cuproptosis-related lncRNAs predict the clinical outcome and immune characteristics of hepatocellular carcinoma.

Cuproptosis, as a novel copper-dependent and non-apoptotic form of cell death, is induced by aggregation of lipoylated mitochondrial proteins and the instability of Fe-S cluster proteins. However, the role of cuproptosis-related long noncoding RNAs (CRLncRNAs) in hepatocellular carcinoma (HCC) has not been clearly elucidated. In this study, we identified and characterized cuproptosis-related lncRNAs in HCC. 343 HCC cases from The Cancer Genome Atlas (TCGA) with gene transcriptome data and clinical data were obtained for analysis after the screening. Univariate and multivariate Cox proportional hazards analyses were performed to establish a prognostic cuproptosis-related lncRNA signature (CRlncSig). We established a prognosis-related model consisting of nine cuproptosis-related lncRNAs: GSEC, AL158166.1, AC005479.2, AL365361.1, AC026412.3, AL031985.3, LINC00426, AC009974.2, AC245060.7, which was validated in the internal cohort. High-risk group stratified by the CRlncSig was significantly related to poor prognosis (p < 0.001). The area under the receiver operating characteristic curve (AUC) of 1 year, 3 years, and 5 years of survival were 0.813, 0.789, and 0.752, respectively. Furthermore, a prognostic nomogram including CRlncSig with clinicopathologic factors was built with favorable predictive power. In addition, GO and KEGG enrichment analysis suggested that CRlncSig was involved in many carcinogenesis and immune-related pathways. Additionally, we found that tumor microenvironment, immune infiltration, immune function, and drug response were significantly different between the high-risk and low-risk groups based on the risk model. These results highlight the value of cuproptosis-related lncRNAs on prognosis for HCC patients and provide insight into molecular and immune features underlying cuproptosis-related lncRNAs, which might play an important role in patient management and immunotherapy.

Cuproptosis scoring model predicts overall survival and assists in immunotherapeutic decision making in pancreatic carcinoma.

Background: Cuproptosis is a newly identified form of non-apoptotic cell death that is associated with the progression and treatment responses in pancreatic adenocarcinoma (PAAD). However, its impact on oncology and tumor microenvironment (TME) remains unclear. Methods: Hub genes were identified using least absolute shrinkage and selection operator (LASSO) Cox regression for 25 newly reported cuproptosis-related regulators and subjected to stepwise regression to obtain cuproptosis-related score (CuRS). Additionally, the clinical significance, functional status, role on TME, and genomic variation of CuRS were further examined systematically. Results: A CuRS model incorporating TRAF2, TRADD, USP21, FAS, MLKL, TNFRSF10B, MAPK8, TRAF5, and RIPK3 was developed. The stability and accuracy of this risk model as an independent prognostic factor for PAAD were confirmed in the training and external validation cohorts. Patients in the high-CuRS group had “cold” tumors with active tumor proliferation and immunosuppression, whereas those in the low-CuRS group comprised “hot” tumors with active immune function and cell killing capacity. Additionally, patients in the high-CuRS group carried fewer genomic copy number variations (CNVs) and greater somatic mutations. Furthermore, patients in the low- and high-CuRS groups exhibited increased sensitivity to immunotherapy and chemotherapy, respectively. Conclusion: We developed and validated a robust CuRS model based on cuproptosis to assess patients’ prognoses and guide clinical decision-making. Overall, the findings of this study are expected to contribute to the comprehensive understanding of cuproptosis and facilitate precise treatment of PAAD.

Analysis of the potential ferroptosis mechanism and multitemporal expression change of central ferroptosis-related genes in cardiac ischemia-reperfusion injury.

Acute myocardial infraction is the most severe type of coronary artery disease and remains a substantial burden to the health care system globally. Although myocardial reperfusion is critical for ischemic cardiac tissue survival, the reperfusion itself could cause paradoxical injury. This paradoxical phenomenon is known as ischemia–reperfusion injury (IRI), and the exact molecular mechanism of IRI is still far from being elucidated and is a topic of controversy. Meanwhile, ferroptosis is a nonapoptotic form of cell death that has been reported to be associated with various cardiovascular diseases. Thus, we explored the potential ferroptosis mechanism and target in cardiac IRI via bioinformatics analysis and experiment. GSE4105 data were obtained from the GEO database and consist of a rat IRI model and control. After identifying differentially expressed ferroptosis-related genes (DEFRGs) and hub genes of cardiac IRI, we performed enrichment analysis, coexpression analysis, drug–gene interaction prediction, and mRNA–miRNA regulatory network construction. Moreover, we validated and explored the multitemporal expression of hub genes in a hypoxia/reoxygenation (H/R)-induced H9C2 cell injury model under different conditions via RT-qPCR. A total of 43 DEFRGs and 7 hub genes (tumor protein p53 [Tp53], tumor necrosis factor [Tnf], hypoxia-inducible factor 1 subunit alpha [Hif1a], interleukin 6 [Il6], heme oxygenase 1 [Hmox1], X-box binding protein 1 [Xbp1], and caspase 8 [Casp8]) were screened based on bioinformatics analysis. The functional annotation of these genes revealed apoptosis, and the related signaling pathways could have association with the pathogenesis of ferroptosis in cardiac IRI. In addition, the expression of the seven hub genes in IRI models were found higher than that of control under different H/R conditions and time points. In conclusion, the analysis of 43 DEFRGs and 7 hub genes could reveal the potential biological pathway and mechanism of ferroptosis in cardiac IRI. In addition, the multitemporal expression change of hub genes in H9C2 cells under different H/R conditions could provide clues for further ferroptosis mechanism exploring, and the seven hub genes could be potential biomarkers or therapeutic targets in cardiac IRI.

γ-Glutamylcysteine Exerts Neuroprotection Effects against Cerebral Ischemia/Reperfusion Injury through Inhibiting Lipid Peroxidation and Ferroptosis.

Ferroptosis is a non-apoptotic form of cell death driven by iron-dependent lipid peroxidation. Recent evidence indicates that inhibiting ferroptosis could alleviate cerebral ischemia/reperfusion (CIR) injury. γ-glutamylcysteine (γ-GC), an intermediate of glutathione (GSH) synthesis, can upregulate GSH in brains. GSH is the co-factor of glutathione peroxidase 4 (GPX4), which is the negative regulator of ferroptosis. In this study, we explored the effect of γ-GC on CIR-induced neuronal ferroptosis and brain injury. We found that γ-GC significantly reduced the volume of cerebral infarction, decreased the loss of neurons and alleviated neurological dysfunction induced by CIR in rats. Further observation showed that γ-GC inhibited the CIR-caused rupture of the neuronal mitochondrial outer membrane and the disappearance of cristae, and decreased Fe2+ deposition and lipid peroxidation in rat cerebral cortices. Meanwhile, γ-GC altered the expression of some ferroptosis-related proteins in rat brains. Mechanistically, γ-GC increased the expression of GSH synthetase (GSS) for GSH synthesis via protein kinase C (PKC)ε-mediated activation of nuclear factor erythroid 2-related factor (Nrf2). Our findings suggest that γ-GC not only serves as a raw material but also increases the GSS expression for GSH synthesis against CIR-induced lipid peroxidation and ferroptosis. Our study strongly suggests that γ-GC has potential for treating CIR injury.

Dexmedetomidine prevents hemorrhagic brain injury by reducing damage induced by ferroptosis in mice

Intracerebral hemorrhage (ICH) is a devastating condition with significant morbidity and mortality for which few effective treatments are clinically available. After ICH, iron overload within the perihaematomal region can induce lethal reactive oxygen species (ROS) production and lipid peroxidation, which contribute to secondary brain injury. An iron-dependent form of non-apoptotic cell death known as ferroptosis was recently identified. Ferroptosis plays an important role in ICH pathology. It is characterized by an accumulation of iron-induced lipid ROS, which leads to intracellular oxidative stress. Dexmedetomidine (DEX), an α2-adrenergic agonist, is widely used for anesthesia, pain control, and intensive care unit sedation. DEX has numerous beneficial activities, including anti-inflammatory, anti-oxidative, and anti-cell death activities. Here, we established a mouse model of ICH using collagenase VII and evaluated the effect of DEX in preventing ICH-induced brain injury. Our study showed that administering DEX reduced the damage induced by ferroptosis after ICH by regulating iron metabolism, amino acid metabolism and lipid peroxidation processes.

Adipocyte-Derived Exosomal MTTP Suppresses Ferroptosis and Promotes Chemoresistance in Colorectal Cancer.

Obesity is closely related to a poor prognosis in patients with advanced colorectal cancer (CRC), but the mechanisms remain unclear. Ferroptosis is a form of nonapoptotic cell death characterized by lipid reactive oxygen species (ROS) accumulation and iron dependency and is associated with the chemoresistance of tumors. Here, it is shown that adipose‐derived exosomes reduce ferroptosis susceptibility in CRC, thus promoting chemoresistance to oxaliplatin. It is found that microsomal triglyceride transfer protein (MTTP) expression is increased in the plasma exosomes of CRC patients with a high body fat ratio, serving as an inhibitor of ferroptosis and reducing sensitivity to chemotherapy. Mechanistically, the MTTP/proline‐rich acidic protein 1 (PRAP1) complex inhibited zinc finger E‐box binding homeobox 1 expression and upregulated glutathione peroxidase 4 and xCT, leading to a decreased polyunsaturated fatty acids ratio and lipid ROS levels. Moreover, experiments are carried out in organoids, and a tumor implantation model is established in obese mice, demonstrating that the inhibition of MTTP increases the sensitivity to chemotherapy. The results reveal a novel intracellular signaling pathway mediated by adipose‐derived exosomes and suggest that treatments targeting secreted MTTP might reverse oxaliplatin resistance in CRC.

In silico identification and verification of ferroptosis-related genes in type 2 diabetic islets.

Type 2 diabetes (T2D) is a major global public health burden, with β-cell dysfunction a key component in its pathogenesis. However, the exact pathogenesis of β-cell dysfunction in T2D is yet to be fully elucidated. Ferroptosis, a recently discovered regulated form of non-apoptotic cell death, plays a vital role in the development of diabetes and its complications. The current study aimed to identify the key molecules involved in β-cell ferroptosis3 in patients with T2D using the mRNA expression profile data of GSE25724 by bioinformatic approaches. The differentially expressed mRNAs (DE-mRNAs) in human islets of patients with T2D were screened using the islet mRNA expression profiling data from the Gene Expression Omnibus and their intersection with ferroptosis genes was then obtained. Ferroptosis-related DE-mRNA functional and pathway enrichment analysis in T2D islet were performed. Using a protein-protein interaction (PPI) network constructed from the STRING database, Cytoscape software identified ferroptosis-related hub genes in the T2D islet with a Degree algorithm. We constructed a miRNA-hub gene network using the miRWalk database. We generated a rat model of T2D to assess the expression of hub genes. A total of 1,316 DE-mRNAs were identified in the islet of patients between T2D and non-T2D (NT2D), including 221 and 1,095 up- and down-regulated genes. Gene set enrichment analysis revealed that the ferroptosis-related gene set was significantly different in islets between T2D and NT2D at an overall level. A total of 33 ferroptosis-related DE-mRNAs were identified, most of which were significantly enriched in pathways including ferroptosis. The established PPI network with ferroptosis-related DE-mRNAs identified five hub genes (JUN, NFE2L2, ATG5, KRAS, and HSPA5), and the area under the ROC curve of these five hub genes was 0.929 in the Logistic regression model. We constructed a regulatory network of hub genes and miRNAs, and the results showed that suggesting that hsa-miR-6855-5p, hsa-miR-9985, and hsa-miR-584-5p could regulate most hub genes. In rat model of T2D, the protein expression levels of JUN and NFE2L2 in pancreatic tissues were upregulated and downregulated, respectively. These results contribute to further elucidation of ferroptosis-related molecular mechanisms in the pathogenesis of β-cell dysfunction of T2D.

A non-canonical vitamin K cycle is a potent ferroptosis suppressor

Ferroptosis, a non-apoptotic form of cell death marked by iron-dependent lipid peroxidation1, has a key role in organ injury, degenerative disease and vulnerability of therapy-resistant cancers2. Although substantial progress has been made in understanding the molecular processes relevant to ferroptosis, additional cell-extrinsic and cell-intrinsic processes that determine cell sensitivity toward ferroptosis remain unknown. Here we show that the fully reduced forms of vitamin K—a group of naphthoquinones that includes menaquinone and phylloquinone3—confer a strong anti-ferroptotic function, in addition to the conventional function linked to blood clotting by acting as a cofactor for γ-glutamyl carboxylase. Ferroptosis suppressor protein 1 (FSP1), a NAD(P)H-ubiquinone reductase and the second mainstay of ferroptosis control after glutathione peroxidase-44,5, was found to efficiently reduce vitamin K to its hydroquinone, a potent radical-trapping antioxidant and inhibitor of (phospho)lipid peroxidation. The FSP1-mediated reduction of vitamin K was also responsible for the antidotal effect of vitamin K against warfarin poisoning. It follows that FSP1 is the enzyme mediating warfarin-resistant vitamin K reduction in the canonical vitamin K cycle6. The FSP1-dependent non-canonical vitamin K cycle can act to protect cells against detrimental lipid peroxidation and ferroptosis.

Ferroptosis in COVID-19-related liver injury: A potential mechanism and therapeutic target.

The outbreak and worldwide spread of coronavirus disease 2019 (COVID-19), which is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has been a threat to global public health. SARS-CoV-2 infection not only impacts the respiratory system but also causes hepatic injury. Ferroptosis, a distinct iron-dependent form of non-apoptotic cell death, has been investigated in various pathological conditions, such as cancer, ischemia/reperfusion injury, and liver diseases. However, whether ferroptosis takes part in the pathophysiological process of COVID-19-related liver injury has not been evaluated yet. This review highlights the pathological changes in COVID-19-related liver injury and presents ferroptosis as a potential mechanism in the pathological process. Ferroptosis, as a therapeutic target for COVID-19-related liver injury, is also discussed. Discoveries in these areas will improve our understanding of strategies to prevent and treat hepatic injuries caused by COVID-19.

Prediction of Prognosis in Patients With Endometrial Carcinoma and Immune Microenvironment Estimation Based on Ferroptosis-Related Genes.

Background: Ferroptosis, a form of non-apoptotic cell death, has aroused worldwide interest in cancer researchers. However, the current study about the correlation between ferroptosis-related genes (FRGs) and endometrial cancer (EC) remains limited. Methods: First, the transcriptome profiling and clinical data of EC patients were downloaded from The Cancer Genome Atlas (TCGA) and Clinical Proteomic Tumor Analysis Consortium (CPTAC) program as the training group and testing group, respectively. FRGs were acquired through literature mining. Then, we used R 4.1.1 software to screen the differently expressed FRGs from TCGA, which was also connected with the prognosis of EC patients. Subsequently, the risk score of each tumor sample was identified by LASSO regression analysis, and we classified these samples into the high- and low-risk groups in the light of the median risk score. Receiver operating characteristic (ROC) curve analysis and Kaplan-Meier analysis were performed to assess the accuracy of this signature. Significantly, the data from CPTAC was used to validate the prediction model externally. Furthermore, we evaluated the immune microenvironment in this model via single-sample gene set enrichment analysis (ssGSEA). Results: Among the 150 FRGs, 6 differentially expressed genes (DEGs) based on TCGA had a relationship with the prognosis of EC patients, namely, TP53, AIFM2, ATG7, TLR4, PANX1 and MDM2. The survival curve indicated a higher survival probability in the low-risk group. Moreover, the FRGs-based signature acted well in the prediction of overall survival (OS). The results of external verification confirmed the prediction model we established. Finally, ssGSEA revealed significant differences in the abundance of 16 immune cells infiltration and the activity of 13 immune functions between different risk groups. Conclusion: We identified a novel ferroptosis-related gene signature which could concisely predict the prognosis and immunotherapy in EC patients.

Inhibitory effects of temozolomide on glioma cells is sensitized by RSL3-induced ferroptosis but negatively correlated with expression of ferritin heavy chain 1 and ferritin light chain

Invasive growth of glioblastoma makes residual tumor unremovable by surgery and leads to disease relapse. Temozolomide is widely used first-line chemotherapy drug to treat glioma patients, but development of temozolomide resistance is almost inevitable. Ferroptosis, an iron-dependent form of non-apoptotic cell death, is found to be related to temozolomide response of gliomas. However, whether inducing ferroptosis could affect invasive growth of glioblastoma cells and which ferroptosis-related regulators were involved in temozolomide resistance are still unclear. In this study, we treated glioblastoma cells with RSL3, a ferroptosis inducer, in vitro (cell lines) and in vivo (subcutaneous and orthotopic animal models). The treated glioblastoma cells with wild-type or mutant IDH1 were subjected to RNA sequencing for transcriptomic profiling. We then analyze data from our RNA sequencing and public TCGA glioma database to identify ferroptosis-related biomarkers for prediction of prognosis and temozolomide resistance in gliomas. Analysis of transcriptome data from RSL3-treated glioblastoma cells suggested that RSL3 could inhibit glioblastoma cell growth and suppress expression of genes involved in cell cycle. RSL3 effectively reduced mobility of glioblastoma cells through downregulation of critical genes involved in epithelial-mesenchymal transition. Moreover, RSL3 in combination with temozolomide showed suppressive efficacy on glioblastoma cell growth, providing a promising therapeutic strategy for glioblastoma treatment. Although temozolomide attenuated invasion of glioblastoma cells with mutant IDH1 more than those with wild-type IDH1, the combination of RSL3 and temozolomide similarly impaired invasive ability of glioblastoma cells in spite of IDH1 status. Finally, we noticed that both ferritin heavy chain 1 and ferritin light chain predicted unfavorable prognosis of glioma patients and were significantly correlated with mRNA levels of methylguanine methyltransferase as well as temozolomide resistance. Altogether, our study provided rationale for combination of RSL3 with temozolomide to suppress glioblastoma cells and revealed ferritin heavy chain 1 and ferritin light chain as biomarkers to predict prognosis and temozolomide resistance of glioma patients.

PPARα alleviates iron overload-induced ferroptosis in mouse liver.

Ferroptosis is an iron‐dependent form of non‐apoptotic cell death implicated in liver, brain, kidney, and heart pathology. How ferroptosis is regulated remains poorly understood. Here, we show that PPARα suppresses ferroptosis by promoting the expression of glutathione peroxidase 4 (Gpx4) and by inhibiting the expression of the plasma iron carrier TRF. PPARα directly induces Gpx4 expression by binding to a PPRE element within intron 3. PPARα knockout mice develop more severe iron accumulation and ferroptosis in the liver when fed a high‐iron diet than wild‐type mice. Ferrous iron (Fe2+) triggers ferroptosis via Fenton reactions and ROS accumulation. We further find that a rhodamine‐based "turn‐on" fluorescent probe(probe1) is suitable for the in vivo detection of Fe2+. Probe1 displays high selectivity towards Fe2+, and exhibits a stable response for Fe2+ with a concentration of 20 μM in tissue. Our data thus show that PPARα activation alleviates iron overload‐induced ferroptosis in mouse livers through Gpx4 and TRF, suggesting that PPARα may be a promising therapeutic target for drug discovery in ferroptosis‐related tissue injuries. Moreover, we identified a fluorescent probe that specifically labels ferrous ions and can be used to monitor Fe2+ in vivo.

Abstract 3011: Development of mitochondrial fission inhibitors in inducing non-apoptotic cell death in triple-negative breast cancer

Abstract Triple-negative breast cancer (TNBC) is the most aggressive subtype of metastatic breast cancer with poor clinical prognosis. Presently used neoadjuvant chemotherapy against TNBC, such as taxanes, and/or anthracyclines show an initial treatment response but follows with drug resistance, tumor relapse, side effects and high proclivity to develop metastases. Recent studies point out that targeting dysregulated mitochondrial dynamics, that is now linked to the tumor initiation, progression, and metastasis in TNBC, as an effective therapeutic strategy. In particular, mitochondrial fission factors such as dynamin-related protein 1 (Drp1) is upregulated in TNBC and is known to affect mitochondrial energetics and alter metabolism which favors tumor progression. We have designed and developed small molecule inhibitors to specifically target Drp1 as a viable therapeutic strategy for metastatic TNBC (mTNBC). We recently identified a new class of structurally constrained thienopyridine (TPH) probes, and particularly a new analog TPH104c that showed higher binding affinity in silico to Drp1 as compared to Mdivi-1, a weak inhibitor of Drp1. Surface plasmon resonance studies suggest that TPH104c binds with Drp1 with high affinity. Similarly, mechanistic studies using Western blotting and immunofluorescence analysis confirmed that TPH104c significantly downregulated the levels of total and phosphorylated form of Drp1 at serine 616 in MDAMB-231 and BT-20 TNBC cells. Interestingly, Drp1 inhibition by TPH104c led to a hitherto unreported form of caspase- and reactive oxygen species (ROS)-independent non-apoptotic form of cell death. Rather than shrinking in size, or formation of apoptotic blebs which are classical features of apoptosis, TPH104c treated TNBC cells were enlarged, rounded, and swollen in size. These cells eventually lost their proliferative ability and were significantly less confluent than control cells. Additionally, in TPH104c-treated cells, neither the mitochondrial membrane potential was lost, nor the caspases were activated as also indicated by a lack of rescue of cell death when incubated with pan-caspase inhibitor. Further studies are in progress to understand the role of Drp1 inhibition in the induction of non-apoptotic cell death which will further help to optimize an effective lead compound for the future pre-clinical development of promising anticancer agents targeting mTNBC. Citation Format: Saloni Malla, Shikha Kumari, David Terrero, Dayanidhi Raman, Amit K. Tiwari. Development of mitochondrial fission inhibitors in inducing non-apoptotic cell death in triple-negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3011.

Ferroptosis: A Potential Therapeutic Target in Acute Kidney Injury.

Ferroptosis is a recently recognized form of nonapoptotic cell death that is triggered by reactive oxidative species (ROS) due to iron overload, lipid peroxidation accumulation, or the inhibition of phospholipid hydroperoxidase glutathione peroxidase 4 (GPX4). Recent studies have reported that ferroptosis plays a vital role in the pathophysiological process of multiple systems such as the nervous, renal, and pulmonary systems. In particular, the kidney has higher rates of O2 consumption in its mitochondria than other organs; therefore, it is susceptible to imbalances between ROS and antioxidants. In ischemia/reperfusion (I/R) injury, which is damage caused by the restoring blood flow to ischemic tissues, the release of ROS and reactive nitrogen species is accelerated and contributes to subsequent inflammation and cell death, such as ferroptosis, as well as apoptosis and necrosis being induced. At the same time, I/R injury is one of the major causes of acute kidney injury (AKI), causing significant morbidity and mortality. This review highlights the current knowledge on the involvement of ferroptosis in AKI via oxidative stress.

Construction and Validation of a 6-Ferroptosis Related Gene Signature for Prognosis and Immune Landscape Prediction in Melanoma.

Ferroptosis is a newly discovered form of non-apoptotic cell death that relies on iron-mediated oxidative damage, playing a crucial role in the progression and therapy resistance of melanoma. Hence, the potential value of ferroptosis-related genes (FRGs) as a prognostic model and therapeutic target in melanoma requires further investigation. In this study, the relationship between FRGs and melanoma was revealed by analyzing the mRNA expression profiles from The Cancer Genome Atlas (TCGA) and Gene Expression Synthesis (GEO). A 6-FRGs signature was constructed by Univariate, multivariate, and lasso Cox regression analyses in the TCGA cohort. The GEO database was used to validate the efficacy of the signature. The protein and mRNA expression level of the signature genes were examined in real-world melanoma tissues via immunohistochemical and quantificational real-time polymerase chain reaction (qRT-PCR). Functional enrichment analysis and immune-related analysis were conducted to identify the potential biological functions and pathways of the signature. Ten putative small molecule drugs were predicted by Connectivity Map (CMAP). As a result, a 6-FRGs signature was constructed to stratify melanoma patients into two risk groups. Compared with the low-risk group, patients in the high-risk group had a worse prognosis and a lower ImmuneScore. Immune-related pathways were enriched in the low-risk group. Immune Function and immune cell infiltration of the low-risk group were significantly higher than that of the high-risk group. The differential expression of these six FRGs in melanoma and adjacent normal tissues was confirmed. Moreover, higher expression of immune checkpoint molecules and a greater sensitivity to immunotherapy were observed in the low-risk group. Some small molecular drugs in the CMAP database hold the potential to treat melanoma. Overall, we identified a novel FRGs signature for prognostic prediction in melanoma. Based on the signature-related immune infiltration landscape found in our study, targeting the FRGs might be a therapeutic alternative for melanoma.

Flake Graphene-Based Nanomaterial Approach for Triggering a Ferroptosis as an Attractive Theranostic Outlook for Tackling Non-Small Lung Cancer: A Mini Review.

Lung cancer is a highly aggressive neoplasm that is now a leading cause of cancer death worldwide. One of the major approaches for killing cancer cells is related with activation of apoptotic cell death with anti-cancer drugs. However, the efficiency of apoptosis induction in tumors is limited. Consequently, the development of other forms of non-apoptotic cell death is up to date challenge for scientists worldwide. This situation motivated us to define the aim of this mini-review: gathering knowledge regarding ferroptosis—newly defined programmed cell death process characterized by the excessive accumulation of iron—and combining it with yet another interesting nanomaterial-based graphene approach. In this manuscript, we presented brief information about non-small lung cancer and ferroptosis, followed by a section depicting the key-features of graphene-based nanomaterials influencing their biologically relevant properties.

Lipid Metabolism and Ferroptosis

Ferroptosis is an oxidative, iron‐dependent form of non‐apoptotic cell death that contributes to several forms of pathology and may be exploitable for cancer therapy. Ferroptosis can be induced using small molecule inhibitors of the plasma membrane cystine/glutamate antiporter system xc‐ or the glutathione‐dependent lipid hydroperoxidase glutathione peroxidase 4 (GPX4). The execution of ferroptosis requires membrane lipid peroxidation, but specific lipids and lipid metabolic enzymes that are involved in this process are only partly characterized. How ferroptosis sensitivity relates to other fundamental cellular processes such as the cell cycle is also unclear. We find that inhibition of the Rb‐E2F cell cycle pathway causes downregulation of specific lipid metabolic enzymes, leading to an increase in polyunsaturated phospholipid abundance. In turn, this metabolic alteration specifically enhances ferroptosis sensitivity. Drugs that inhibit Rb‐E2F pathway function synergize with a ferroptosis‐inducing small molecule to arrest tumor growth in vivo. These results suggest that ferroptosis sensitivity may be linked to cell cycle progression through specific alterations in membrane phospholipid composition.

Iron Transporters and Ferroptosis in Malignant Brain Tumors.

Malignant brain tumors represent approximately 1.5% of all malignant tumors. The survival rate among patients is relatively low and the mortality rate of pediatric brain tumors ranks first among all childhood malignant tumors. At present malignant brain tumors remain incurable. Although some tumors can be treated with surgery and chemotherapy, new treatment strategies are urgent owing to the poor clinical prognosis. Iron is an essential trace element in many biological processes of the human body. Iron transporters play a crucial role in iron absorption and transport. Ferroptosis, an iron-dependent form of nonapoptotic cell death, is characterized by the accumulation of lipid peroxidation products and lethal reactive oxygen species (ROS) derived from iron metabolism. Recently, compelling evidence has shown that inducing ferroptosis of tumor cells is a potential therapeutic strategy. In this review, we will briefly describe the significant regulatory factors of ferroptosis, iron, its absorption and transport under physiological conditions, especially the function of iron transporters. Then we will summarize the relevant mechanisms of ferroptosis and its role in malignant brain tumors, wherein the role of transporters is not to be ignored. Finally, we will introduce the current research progress in the treatment of malignant brain tumors by inducing ferroptosis in order to explain the current biological principles of potential treatment targets and treatment strategies for malignant brain tumors.

Ferroptosis contributes to methylmercury-induced cytotoxicity in rat primary astrocytes and Buffalo rat liver cells

ObjectiveFerroptosis is an iron-dependent nonapoptotic form of cell death, characterized by iron accumulation and lipid peroxidation. However, the role of ferroptosis in methylmercury (MeHg)-induced cytotoxicity has yet to be fully characterized. The purpose of this study was to investigate the role of ferroptosis in MeHg-induced cytotoxicity in both brain and liver cells. MethodsThe effects of MeHg on cell viability, cytotoxicity, intracellular iron content, reduced glutathione (GSH) content, ferroptosis-related proteins, cytosolic and lipid reactive oxygen species (ROS) generation were determined in rat primary astrocytes (AST) and Buffalo Rat Liver (BRL) cells in the absence or presence of the ferroptosis inhibitors deferoxamine (DFO) or ferrostatin-1 (Fer-1). ResultsMeHg treatment decreased cell viability and increased cytotoxicity in AST and BRL cells. MeHg induced ferroptosis in AST and BRL cells was reflected by increased cytosolic ROS, lipid ROS and intracellular iron content, all of which were inhibited by the ferroptosis inhibitors DFO and/or Fer-1. MeHg inhibited the expression of ferritin heavy chain 1 (FTH1). Furthermore, MeHg treatment decreased the expression of glutathione peroxidase 4 (GPx4) without altering solute carrier family 7 member 11 (SLC7A11). DFO and Fer-1 significantly increased the expression of GPx4, yet had no effect on SLC7A11 upon MeHg treatment. ConclusionsOur novel results are consistent with ferroptosis as a key event mediating MeHg-induced toxicity, inhibiting GPx4 in AST and BRL cells. Ferroptosis may offer a new target for attenuating MeHg-induced toxic injury.

COVID-19-Related Brain Injury: The Potential Role of Ferroptosis.

The COVID-19 pandemic has caused devastating loss of life and a healthcare crisis worldwide. SARS-CoV-2 is the causative pathogen of COVID-19 and is transmitted mainly through the respiratory tract, where the virus infects host cells by binding to the ACE2 receptor. SARS-CoV-2 infection is associated with acute pneumonia, but neuropsychiatric symptoms and different brain injuries are also present. The possible routes by which SARS-CoV-2 invades the brain are unclear, as are the mechanisms underlying brain injuries with the resultant neuropsychiatric symptoms in patients with COVID-19. Ferroptosis is a unique iron-dependent form of non-apoptotic cell death, characterized by lipid peroxidation with high levels of glutathione consumption. Ferroptosis plays a primary role in various acute and chronic brain diseases, but to date, ferroptosis in COVID-19-related brain injuries has not been explored. This review discusses the mechanisms of ferroptosis and recent evidence suggesting a potential pathogenic role for ferroptosis in COVID-19-related brain injury. Furthermore, the possible routes through which SARS-CoV-2 could invade the brain are also discussed. Discoveries in these areas will open possibilities for treatment strategies to prevent or reduce brain-related complications of COVID-19.