Ferroptosis-related Gene Research Articles

Ferroptosis-related gene signature for predicting prognosis and identifying potential therapeutic drug in EGFR wild-type lung adenocarcinoma

Epidermal growth factor receptor wild type lung adenocarcinoma (EGFRWT LUAD) still has limited treatment options and unsatisfactory clinical outcomes. Ferroptosis, as a form of cell death, has been reported to play a dual role in regulating tumor cell survival. In this study, we constructed a 3-ferroptosis-gene signature, FeSig, and verified its accuracy and efficacy in predicting EGFRWT LUAD prognosis at both the RNA and protein levels. Patients with higher FeSig scores were found to have worse clinical outcomes. Additionally, we explored the relationship between FeSig and tumor microenvironment, revealing that enhanced interactions between fibroblasts and tumor cells in FeSighigh patients causing tumor resistance to ferroptosis. To address this challenge, we screened potential drugs from NCI-60 (The US National Cancer Institute 60 human tumour cell line anticancer drug screen) and Connectivity map database, ultimately identifying 6-mercatopurine (6-MP) as a promising candidate. Both in vitro and in vivo experiments demonstrated its efficacy in treating FeSighigh EGFRWT LUAD tumor models. In summary, we develop a novel FeSig for predicting prognosis and guiding drug application.

Genetic profile of ferroptosis in non-small cell lung carcinoma and pharmaceutical options for ferroptosis induction.

Lung cancer (LC) is the leading cause of cancer-related deaths and the second most commonly diagnosed malignancy worldwide. Lung adenocarcinoma (LUAD) and lung squamous cell LC (LUSCC) are the most common subtypes of non-small cell LC (NSCLC). Early diagnosis of LC can be challenging due to a lack of biomarkers. The overall survival (OS) of patients with NSCLC is still poor despite the enormous efforts that have been made to develop novel treatments. Understanding fundamental molecular and genetic mechanisms is necessary to develop new therapeutic approaches for NSCLC. A recently identified type of programmed cell death known as ferroptosis is one potential approach. Ferroptosis causes oxidative damage and the death of cancerous cells by peroxidizing unsaturated phospholipids and accumulating reactive oxygen species (ROS) in an iron-dependent manner. Ferroptosis-related gene (FRG) signatures have recently been evaluated for their ability to predict patient OS and prognosis. These analyses show FRGs are involved in cancer progression, and may serve as promising biomarkers for tumor diagnosis and therapy. Moreover, we summarize the current pharmaceutical options of ferroptosis induction and their underlying molecular mechanism in LC. Therefore, this review aims to provide a comprehensive summary of FRG-based prognostic models, their associated metabolic and signaling pathways, and promising therapeutic options for ferroptosis induction in NSCLC.

Construction and multiple validations of a robust ferroptosis-related prognostic model in bladder cancer: A comprehensive study.

Ferroptosis is iron-dependent programmed cell death that inhibits tumor growth, particularly in traditional treatment-resistant tumors. Prognostic models constructed from ferroptosis-related genes are lacking; prognostic biomarkers remain insufficient. We acquired gene expression data and corresponding clinical information for bladder cancer (BC) samples from public databases. Ferroptosis-related genes from the ferroptosis database were screened for clinical predictive value. We validated gene expression differences between tumors and normal tissues through polymerase chain reaction and western blotting. Gene ontology and Kyoto encyclopedia of genes and genomes enrichment analyses were conducted to explore signaling pathways affecting the overall survival of patients with BC. CIBERSORT was used to quantify the infiltration of 22 immune cell types. We identified 6 genes (EGFR, FADS1, ISCU, PGRMC1, PTPN6, and TRIM26) to construct the prognostic risk model. The high-risk group had a poorer overall survival than the low-risk group. Receiver operating characteristic curves demonstrated excellent predictive accuracy. The validation cohort and 3 independent datasets confirmed the models' general applicability and stability. BC tissues had elevated FADS1, PTPN6, and TRIM26 mRNA and protein levels and decreased ISCU levels. Enrichment analysis indicated that neurosecretory activity might be the main pathway affecting the overall survival. High- and low-risk groups had significantly different immune cell infiltration. Specific ferroptosis-related gene expression was associated with immune cell infiltration levels. The risk score was significantly correlated with patients' clinical characteristics. A novel, widely applicable risk model with independent predictive value for the prognosis of patients with BC was established; candidate molecules for future BC research were identified.

ALKBH5 modulation of ferroptosis in recurrent miscarriage: implications in cytotrophoblast dysfunction.

As one of the most common and abundant internal modifications of eukaryotic mRNA, N6-methyladenosine (m6A) modifications are closely related to placental development. Ferroptosis is a newly discovered form of programmed cell death. During placental development, placental trophoblasts are susceptible to ferroptosis. However, the interactions of m6A and ferroptosis in trophoblast physiology and injury are unclear. Recurrent miscarriage (RM) was selected as the main gestational disease in this study. Published data (GSE76862) were used to analyze the gene expression profiles in patients with RM. The extent of m6A modification in total RNA of villous tissues between patients with RM and healthy controls (HC) was compared. ALKBH5 (encoding AlkB homolog 5, RNA demethylase) was selected as the candidate gene for further research. Quantitative real-time reverse transcription PCR, western blotting, and immunohistochemistry (IHC) confirmed the elevated expression of ALKBH5 in the cytotrophoblasts of patients with RM. Then, cell counting kit-8 assays, glutathione disulfide/glutathione quantification, 2',7'-dichlorfluorescein-diacetate staining, and malonaldehyde assays were used to explore the alterations of ferroptosis-related characteristics following RAS-selective lethal (RSL3) stimulation after overexpression of ALKBH5. Thereafter, we re-analyzed the published RNA sequencing data upon knockdown of ALKBH5, combined with published tissue RNA-seq data, and FTL (encoding ferritin light chain) was identified as the ferroptosis-related gene in cytotrophoblasts of patients with RM that is regulated by ALKBH5. Finally, western blotting and IHC confirmed the increased expression of FTL in the cytotrophoblasts from patients with RM. Total m6A levels were decreased in patients with RM. The most significant differentially m6A-related gene was ALKBH5, which was increased in patients with RM. In vitro cell experiments showed that treatment with RSL3 resulted in increased cell death and upregulated ALKBH5 expression. Overexpression of ALKBH5 alleviated RSL3-induced HTR8 cell death and caused decreased levels of intracellular oxidation products. Published transcriptome sequencing revealed that FTL was the major ferroptosis-related gene regulated by ALKBH5 in the villous tissues of patients with RM. Consistent with the expression of ALKBH5, FTL was increased by RSL3-induction and increased in patients with RM. Elevated ALKBH5 alleviated RSL3-induced cytotrophoblast cell death by promoting the expression of FTL in patients with RM. Our results supported the view that ALKBH5 is an important regulator of the ferroptosis-related etiology of RM and suggested that ALKBH5 could be responsible for epigenetic aberrations in RM pathogenesis.

Ferroptosis related CPT1A and GDF15 gene polymorphisms are risk factors for lung adenocarcinoma: A case-control study

BackgroundFerroptosis is not only a consequence of inflammation, but also a dynamic process. Recent bioinformatics analysis suggests that ferroptosis related genes might be associated with lung adenocarcinoma (LUAD). CPT1A and GDF15 are critical for the process of ferroptosis and development of inflammation; however, little study focused on the mutation level of these genes in patients with LUAD. MethodsThe candidate SNPs in CPT1A and GDF15 were genotyped in 320 pairs of LUAD patients and controls using Mass ARRAY platform. Moreover, the different expression of CPT1A and GDF15 in LUAD cases and healthy controls were validated by qRT-PCR and ELISA. ResultsThe rs80356779 G > A, rs3019594 C > T, rs888663 T > G and rs4808793 G > C all exhibited an increased risk of the disease (p < 0.05). Moreover, the rs80356779-GA, rs3019594-TT, rs888663-TG and rs4808793-CC genotypes were all related to different levels of increase in LUAD risk (p < 0.05). Genetic model results showed that rs80356779 G > A, rs888663 T > G and rs4808793 G > C were associated with LUAD susceptibility under dominant and additive models (p < 0.05), while rs3019594 C > T was correlated with an elevated risk of the disease in all three models (p < 0.05). Additionally, patients with rs80356779 G > A and rs3019594 C > T exhibited lower expression and serum concentration of CPT1A compared with wile types, and patients with rs888663 T > G and rs4808793 G > C exhibited higher serum and expression level of GDF15. ConclusionThe results provided new clues for the role of ferroptosis in LUAD and new potential targets for screening of susceptible population.

Erratum: Identification of a ferroptosis-related gene signature for the prognosis of pediatric neuroblastoma

Erratum: Identification of a ferroptosis-related gene signature for the prognosis of pediatric neuroblastoma

Diosgenin ameliorating non-alcoholic fatty liver disease via Nrf2-mediated regulation of oxidative stress and ferroptosis.

This study aimed to investigate the mechanisms through which diosgenin inhibits the pathogenesis of non-alcoholic fatty liver disease, focusing particularly on ferroptosis-related pathways and its reliance on nuclear factor erythroid 2-related factor 2. Using a rat model, we showed diosgenin's efficacy in reducing lipid deposition throughout the body and examined its impact on ferroptosis-related gene expression in vivo. Moreover, in vitro experiments using human hepatocellular liver carcinoma cell line cells were conducted to assess oxidative stress and ferroptosis levels. Diosgenin decreased lipid accumulation and steatosis; lowered serum levels of total cholesterol, triglycerides, low-density lipoprotein cholesterol, glutamic pyruvic transaminase and glutamic oxaloacetic transaminase; reduced interleukin-1β and tumour necrosis factor-α; diosgenin decreased malondialdehyde levels; and increased serum superoxide dismutase levels in a rat model of high-fat diet-induced non-alcoholic fatty liver disease. Diosgenin upregulated the expression of nuclear factor erythroid 2-related factor 2 and its downstream ferroptosis-related genes to inhibit ferroptosis in the livers of rats with non-alcoholic fatty liver disease. Diosgenin decreased reactive oxygen species levels and enhanced the expression of ferroptosis-related genes in human hepatocellular liver carcinoma cells induced by free fatty acids, with its effects being dependent on nuclear factor erythroid 2-related factor 2. This study highlights the potential of diosgenin from Dioscoreaceae plants in mitigating oxidative stress and ferroptosis levels through nuclear factor erythroid 2-related factor 2 regulation, offering novel insights into the treatment of non-alcoholic fatty liver disease and other metabolic disorders through traditional Chinese medicine.

Characterization of a ferroptosis-related gene signature predicting survival and immunotherapeutic response in lung adenocarcinoma.

Lung cancer remains the leading cause of cancer-related death worldwide, and drug resistance represents the main obstacle responsible for the poor mortality and prognosis. Here, to identify a novel gene signature for predicting survival and drug response, we jointly investigated RNA sequencing data of lung adenocarcinoma patients from TCGA and GEO databases, and identified a ferroptosis-related gene signature. The signature was validated in the validation set and two external cohorts. The high-risk group had a reduced survival than the low-risk group (P < 0.05). Moreover, the established gene signature was associated with tumor mutation burden, microsatellite instability, and response to immune checkpoint blockade. In addition, four candidate oncogenes (RRM2, SLC2A1, DDIT4, and VDAC2) were identified to be candidate oncogenes using in silico and wet experiments, which could serve as potential therapeutic targets. Collectively, this study developed a novel ferroptosis-related gene signature for predicting prognosis and drug response, and identified four candidate oncogenes for lung adenocarcinoma.

Selenium alleviates dextran sulfate sodium-induced colitis and inhibits ferroptosis of intestinal epithelial cells via upregulating glutathione peroxidase 4.

Selenium, an essential micronutrient for humans, has been shown to be protective against ulcerative colitis (UC), but the exact mechanism remains unclear. The role of selenium, protecting against ferroptosis of intestinal epithelial cells (IECs) in colitis, was investigated in this current study. Serum selenium level and ferroptosis-related gene expression in the colonic mucosa were measured in UC patients and healthy controls. The effects of sodium selenite supplementation on experimental colitis were investigated in dextran sulfate sodium (DSS)-treated mice. The influence of sodium selenite on IEC ferroptosis was evaluated through assessing cell death rate, intracellular ferrous iron content, lipid reactive oxygen species level, and mitochondrial membrane damage of DSS-treated Caco-2 cells. Moreover, glutathione peroxidase 4 (GPX4) and acyl-CoA synthetase long-chain family member 4, ferroptosis-related genes, were detected in Caco-2 cells and mouse intestines. Serum selenium was decreased in UC patients in comparison with healthy individuals. Additionally, serum selenium level was negatively correlated with disease activity and was associated with clinical inflammation and nutrition indicators. The expression of GPX4 in the mucosa of UC was positively correlated with serum selenium level. The in vivo experiments showed that selenium treatment ameliorated DSS-induced colitis and inhibited ferroptosis in IECs. The in vitro results suggested that selenium supplementation inhibited DSS-induced ferroptosis in Caco-2 cells. GPX4 was upregulated after selenium supplementation both in vivo and in vitro. Serum selenium level was associated with IEC ferroptosis in UC patients. Selenium supplementation alleviates DSS-induced colitis and inhibits ferroptosis in IECs by upregulating the expression of GPX4.

Investigating the potential risk of cadmium exposure on seizure severity and anxiety-like behaviors through the ferroptosis pathway in epileptic mice: An integrated multi-omics approach

Cadmium, a toxic heavy metal from industrial activities, poses a neurotoxic risk, especially to children. While seizures are common in children, the link between cadmium and seizure activity is unclear. Ferroptosis, an iron-dependent cell death, is key in seizure-induced hippocampal damage and related anxiety. This study aims to elucidate these mechanisms and assess the broader implications of cadmium exposure. Our research contributes in three significant areas: Firstly, through a combination of observational studies in long-term cadmium-exposed workers, Mendelian randomization analysis, NHANES analysis, urinary metabolomics, and machine learning analysis, we explored the impact of long-term cadmium exposure on inflammatory cytokines, ferroptosis-related gene expression, and lipid and iron metabolism. Secondly, by harnessing public databases for human disorders and metal-associated gene targets, alongside therapeutic molecular analyses, we identified critical human gene targets for cadmium toxicity in seizures and proposed melatonin as a promising therapeutic agent. Finally, utilizing mouse behavioral assays, T2 MRI, and MRS, we provide evidence of how prolonged cadmium exposure disrupts iron and lipid metabolism in the brain, triggering ferroptosis in the hippocampus.

Ferroptosis-Related Gene Signature for Prognosis Prediction in Acute Myeloid Leukemia and Potential Therapeutic Options.

Limited data were available to understand the significance of ferroptosis in leukemia prognosis, regardless of the genomic background. RNA-seq data from 151 AML patients were analyzed from The Cancer Genome Atlas (TCGA) database, along with 70 healthy samples from the Genotype-Tissue Expression (GTEx) database. Ferroptosis-related genes (FRGs) features were constructed by multivariate COX regression analysis and risk scores were calculated for each sample and a novel prediction model was identified. The validation was carried out using data from 35 AML patients and 13 healthy controls in our cohort. Drug sensitivity analysis was conducted on various chemotherapeutic drugs. A signature of 10 FRGs was identified, as prognostic predictors for AML, and the risk scores were calculated to constructed the prognostic features of FRGs. Significantly lower overall survival was observed in the high-risk group. The predictive ability of these features for AML prognosis was confirmed using Cox regression analysis, ROC curves, and DCA. The prediction model performed well in our clinical practices, and had its potential superiority when comparing to classical NCCN risk stratification. Multiple chemotherapy drugs, including paclitaxel, dactinomycin, cisplatin, etc. had a lower IC50 in FRGs high-risk group than low-risk group. The AML prognosis model based on FRGs accurately predicts AML prognosis and drug sensitivity, and the drugs identified worthy further investigation.

Ferroptosis-related gene signature predicts prognosis and immune microenvironment in prostate cancer.

Ferroptosis, an iron-dependent form of programmed cell death, significantly impacts cancer, yet its link to prostate cancer (PCa) prognosis remains underexplored. This study aims to develop and validate a ferroptosis-related gene signature to predict PCa prognosis and immune microenvironment differences, potentially identifying therapeutic targets. RNA-sequencing data of 478 PCa patients and corresponding clinical data were downloaded from The Cancer Genome Atlas (TCGA) database. We investigated the disease-free survival (DFS) rates of the high- and low-risk groups using the Kaplan-Meier method. Functional differences between the high- and low-risk groups were investigated by a gene set enrichment analysis (GSEA), and Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses. The link between ferroptosis risk score and immune status was examined using CIBERSORT. The expression levels of core prognostic genes in benign prostatic hyperplasia (BPH) and PCa were verified using quantitative real-time polymerase chain reaction (qRT-PCR), Western blot, and immunohistochemistry (IHC). A novel ferroptosis-related prognostic gene signature was established and tested in the Gene Expression Omnibus (GEO) database based on univariate and multivariate Cox regression analyses. Patients with PCa were classified into high- and low-risk groups based on this ferroptosis signature. Patients in the high-risk group had worse outcomes than those in the low-risk group. The predictive accuracy of the model was demonstrated by a receiver operating characteristic (ROC) analysis. An additional enrichment analysis of TCGA cohort revealed the immune-related pathways were significantly upregulated in the high-risk group, with areas under the curve (AUCs) of 0.85 at 1 year, 0.82 at 3 years, and 0.76 at 5 years. In the GEO cohort, the AUCs reached 0.69 at 1 year, 0.74 at 3 years, and 0.75 at 5 years. An additional enrichment analysis indicated a significant upregulation of cytokine-related pathways, immune receptor activity, and other immune-related pathways in the high-risk group. Furthermore, the analysis revealed that the proportions of mast cells and plasma cells were significantly lower in the high-risk group compared to the low-risk group of PCa patients. Conversely, the proportion of regulatory T cells (Tregs) was significantly higher in the high-risk group than in the low-risk group. According to the qRT-PCR, Western blot, and IHC results, DRD4, SRC, AKR1C2, and AIFM2 expression was significantly higher in PCa than BPH. We also showed that the ferrostatin 1-treated LNCaP cells had higher expression levels of DRD4, SRC, and AKR1C2. A prognostic signature of eight ferroptosis-related genes (FRGs) that may accurately predict PCa patient outcomes was constructed and validated. FRGs may contribute to anti-tumor immunity and serve as therapeutic targets in PCa.

Ferroptosis-related gene transferrin receptor protein 1 expression correlates with the prognosis and tumor immune microenvironment in cervical cancer.

Ferroptosis is a non-apoptotic iron-dependent form of cell death implicated in various cancer pathologies. However, its precise role in tumor growth and progression of cervical cancer (CC) remains unclear. Transferrin receptor protein 1 (TFRC), a key molecule associated with ferroptosis, has been identified as influencing a broad range of pathological processes in different cancers. However, the prognostic significance of TFRC in CC remains unclear. The present study utilized bioinformatics to explore the significance of the ferroptosis-related gene TFRC in the progression and prognosis of CC. We obtained RNA sequencing data and corresponding clinical information on patients with CC from The Cancer Genome Atlas (TCGA), Genotype Tissue Expression (GTEx) and Gene Expression Omnibus (GEO) databases. Using least absolute shrinkage and selection operator (LASSO) Cox regression, we then generated a multigene signature of five ferroptosis-related genes (FRGs) for the prognostic prediction of CC. We investigated the relationship between TFRC gene expression and immune cell infiltration by employing single-sample GSEA (ssGSEA) analysis. The potential functional role of the TFRC gene was evaluated through gene set enrichment analysis (GSEA). Immunohistochemistry and qPCR was employed to assess TFRC mRNA and protein expression in 33 cases of cervical cancer. Furthermore, the relationship between TFRC mRNA expression and overall survival (OS) was investigated in patients. CC samples had significantly higher TFRC gene expression levels than normal tissue samples. Higher TFRC gene expression levels were strongly associated with higher cancer T stages and OS events. The findings of multivariate analyses illustrated that the OS in CC patients with high TFRC expression is shorter than in patients with low TFRC expression. Significant increases were observed in the levels of TFRC mRNA and protein expression in patients diagnosed with CC. Increased TFRC expression in CC was associated with disease progression, an unfavorable prognosis, and dysregulated immune cell infiltration. In addition, it highlights ferroptosis as a promising therapeutic target for CC.

Identification of the ferroptosis-related gene signature and the associated regulation axis in lung cancer and rheumatoid arthritis.

Patients with Rheumatoid arthritis (RA) have an elevated risk of lung cancer compared to the healthy population. However, there are few studies on the relationship between RA and lung adenocarcinoma (LUAD), especially the mechanisms at the genetic level. In this study, we investigated the link between RA and LUAD regarding Ferroptosis-Related Genes. The RNA-seq data of RA (GSE77298 and GSE 82107) and LUAD(GSE75037) in the Gene Expression Omnibus (GEO) database were obtained. 259 ferroptosis-related genes were obtained from the website ( http://www.zhounan.org/ferrdb/ ).The differential genes obtained from the RA and LUAD datasets were intersected with ferroptosis-related genes to obtain the ferroptosis-related differentially expressed genes (FRDEGs). Next, the mRNA-miRNA network was constructed, then Gene Set Enrichment Analysis (GSEA) for target genes were performed. The CIBERSORT algorithm was used to analyze the immune infiltration. Finally, the results were validated using external datasets (GSE89408 and GSE48780) and The Cancer Genome Atlas (TCGA) dataset. We obtained FRDEGs common to LUAD and RA: FANCD2, HELLS, RRM2, G6PD, VLDLR. These five genes play important roles in the progression of RA and LUAD. They also hold great diagnostic value for both diseases. Also, we found that LUAD and RA share common signaling pathways and similar immune mechanisms.

Machine learning identifies key cells and therapeutic targets during ferroptosis after spinal cord injury.

Ferroptosis, a type of cell death that mainly involves iron metabolism imbalance and lipid peroxidation, is strongly correlated with the phagocytic response caused by bleeding after spinal cord injury. Thus, in this study, bulk RNA sequencing data (GSE47681 and GSE5296) and single-cell RNA sequencing data (GSE162610) were acquired from gene expression databases. We then conducted differential analysis and immune infiltration analysis. Atf3 and Piezo1 were identified as key ferroptosis genes through random forest and least absolute shrinkage and selection operator algorithms. Further analysis of single-cell RNA sequencing data revealed a close relationship between ferroptosis and cell types such as macrophages/microglia and their intrinsic state transition processes. Differences in transcription factor regulation and intercellular communication networks were found in ferroptosis-related cells, confirming the high expression of Atf3 and Piezo1 in these cells. Molecular docking analysis confirmed that the proteins encoded by these genes can bind cycloheximide. In a mouse model of T8 spinal cord injury, low-dose cycloheximide treatment was found to improve neurological function, decrease levels of the pro-inflammatory cytokine inducible nitric oxide synthase, and increase levels of the anti-inflammatory cytokine arginase 1. Correspondingly, the expression of the ferroptosis-related gene Gpx4 increased in macrophages/microglia, while the expression of Acsl4 decreased. Our findings reveal the important role of ferroptosis in the treatment of spinal cord injury, identify the key cell types and genes involved in ferroptosis after spinal cord injury, and validate the efficacy of potential drug therapies, pointing to new directions in the treatment of spinal cord injury.

Exposure to volatile ferroptosis inhibitor, TEMPO, reduced cutaneous ischemia-reperfusion injury progression to pressure ulcer formation in a mouse model

BackgroundIschemia– reperfusion (I/R) injury-induced oxidative stress is a key factor in the pathogenesis of pressure ulcer formation. Ferroptosis is an iron-dependent programmed cell death that connects oxidative stress and inflammation in various diseases. Recent studies revealed the protective effect of inhibition of ferroptosis in I/R injury. However, the role of ferroptosis in cutaneous I/R injury remains elusive. ObjectiveTo assess the role of ferroptosis in the progression of cutaneous I/R injury. MethodsCutaneous I/R injury experiments and histopathological studies were performed in wild-type mice with or without exposure to volatile ferroptosis inhibitor, TEMPO (2,2,6,6-Tetramethylpiperidine-1-oxyl). The suppressive effects of TEMPO on ferroptosis inducing cell death and oxidative stress were examined in vitro. ResultsInhibition of ferroptosis with TEMPO significantly reduced ulcer formation after cutaneous I/R injury. Fluctuated ferroptosis markers, such as GPX4, ACSL4, and 4-HNE expression in the I/R skin site, were reversed by TEMPO treatment. Inhibition of ferroptosis reduced apoptosis, CD3+ infiltrating lymphocytes, and improved vascularity in the I/R skin site. Inhibition of ferroptosis also suppressed the enhancement of Nrf2 activation. In vitro, ferroptosis and the activation of ferroptosis-related gene expression by RSL3 stimulation were markedly ameliorated by TEMPO treatment in mouse fibroblasts. Inhibiting ferroptosis also suppressed the elevation of the mRNA levels of NOX2 and HO-1 caused by ferroptosis. ConclusionCutaneous I/R injury-induced ferroptosis likely promotes cell death, vascular loss, infiltration of inflammatory cells, and oxidative stress. The inhibition of ferroptosis with TEMPO might have potential clinical application as novel therapeutic agent for cutaneous I/R injury.

Ferroptosis-Related Gene Signatures in Epilepsy: Diagnostic and Immune Insights.

Epilepsy is characterized by a multifaceted aetiology. Ferroptosis has recently been implicated in seizure pathophysiology, although its mechanistic role in epilepsy remains obscure. We examined the roles of ferroptosis-related genes (FRGs) in epilepsy cohorts from the GSE143272 dataset. We investigated the associations between gene expression and the immune response by performing CIBERSORT and MCP-counter analyses. By employing unsupervised consensus clustering and weighted gene coexpression network analysis (WGCNA), we delineated robust gene clusters across cohorts. Single-cell RNA sequencing data from the GSE201048 dataset provided insights into the interactions between pivotal ferroptosis-related genes and immune cells. Additionally, we employed qRT‒PCR technology to measure the levels of these central genes in the tissues of epileptic patients and mice. Our findings revealed seven pivotal genes (TFRC, POR, PTGS2, RELA, PGD, TRIM21, and QSOX1) at the forefront in epilepsy specimens. A diagnostic model harnessing these genes exhibited substantial efficacy (AUC = 0.913). Similarly, the qRT‒PCR analysis of samples from epileptic patients and mouse epileptic brain tissues substantiated these findings. Stratification of 91 patients with epilepsy via WGCNA, based on gene expression, revealed distinct immunological profiles. The scRNA-seq data further indicated increased expression of central genes in macrophages and microglia. Notably, these cells and those with elevated ferroptosis scores were significantly enriched in inflammation-related pathways. These findings support the strong involvement of FRGs in the pathogenesis of epilepsy, particularly neuroinflammation. These central genes hold promise as novel diagnostic biomarkers for epilepsy.

Quercetin Attenuates Acute Kidney Injury Caused by Cisplatin by Inhibiting Ferroptosis and Cuproptosis.

Ferroptosis, an iron- and ROS-dependent form of regulated cell death. Cuproptosis is a novel form of cellular demise mode. Quercetin, a natural flavonoid, has demonstrated a range of pharmacological activities, including anti-cancer, anti-inflammatory, and antioxidant properties. In this research, we investigated the quercetin effect on cisplatin-induced acute kidney and its mechanism associated ferroptosis and cuproptosis. The HK-2 cells were used in this research. Cell viability was evaluated using the CCK-8 assay. Acute kidney injury (AKI) models were established to perform in vivo experiments. Renal tissue homogenate was used to determine ROS, LPO, MDA, PA, etc., to assess ferroptosis and cuproptosis. To perform bioinformatic analysis, microarray data from the GEO database was utilized. Real-time PCR analysis and ELISA was explored the mechanism of ferroptosis and cuproptosis. We found that ferroptosis and cuproptosis in AKI were abnormally activated caused by cisplatin, and that quercetin attenuated AKI by inhibiting ferroptosis and cuproptosis. QCT suppressed ferroptosis by reducing malondialdehyde (MDA) and ROS levels and increasing glutathione (GSH) levels and alleviated cuproptosis by reducing copper ion, pyruvate (PA) and HSP70 levels. Moreover, bioinformatic analysis revealed that the ferroptosis-related gene SLC7A11 and the cuproptosis-related genes ATP7B and GLS were the differential expression genes. And QCT significantly increased the expression or activity of SLC7A11, GPX4, ATP7B, and GLS in Cis-AKI mice. Our findings highlight the clinical importance of quercetin, which guards against cisplatin-induced acute kidney injury by suppressing ferroptosis and cuproptosis.

Identification of a ferroptosis-related gene signature for the prognosis of pediatric neuroblastoma.

Ferroptosis-related genes are correlated with the prognosis of patients with neuroblastoma (NB) remains unknown. This study aims to establish a prognostic ferroptosis-related gene model for predicting prognostic value in pediatric NB patients. The gene expression array and clinical characteristics of NB were downloaded from a public database. Correlations between ferroptosis-related genes and drug responses were analyzed by Childhood Cancer Therapeutics. The prognostic model was constructed by least absolute shrinkage and selection operator (LASSO) Cox regression and was validated in NB patients from the ICGC cohort. The survival analysis was performed by Cox regression analysis. single-sample gene set enrichment analysis (ssGSEA) was used to quantify the immune cell infiltration correlation. Overall, 70 genes were identified as ferroptosis-related differentially expressed genes (DEGs) from 247 samples. Then, 13 ferroptosis-related genes were correlated with OS in the univariate Cox regression analysis. Five prognostic ferroptosis-related DEGs (pFR-DEGs) (STEAP3, MAP1LC3A, ULK2, MTOR and TUBE1), which were defined as the intersection of DEGs and prognostic ferroptosis-related genes, were identified and utilized to construct the prognostic signature. The correlation between five pFR-DEGs and drug responses was analyzed, and the box plots indicated that MTOR gene expression was highest, suggesting that MTOR expression is related to progressive NB disease. The receiver operating characteristic (ROC) curve showed that the model had moderate predictive power. The survival analysis indicated that the high-risk group had poor overall survival (OS) (P=2.087×10-06). Univariate and multivariate analyses identified the risk score as a significant prognostic risk factor [P=0.003, hazard ratio (HR) =1.933]. Immune cell infiltration correlation analysis showed that the high-risk group was related to more immune cells. The present study indicated a difference in ferroptosis-related gene expression between low- and high-risk NB patients. The ferroptosis-related signature could serve as a prognostic prediction tool. Additionally, immune infiltration might play an important role in different risk groups for NB patients.

A signature of four ferroptosis-related genes in laryngeal squamous cell carcinoma.

Laryngeal squamous cell carcinoma (LSCC) prognosis has not improved significantly in the past few decades, and more effective treatments are needed to be explored. Ferroptosis is a newly discovered kind of regulated cell death in recent years, which is related to tumor immunity and can used to treat tumors. Therefore, the prognostic value of ferroptosis-related genes in laryngeal cancer needs further clarification. In this study, the mRNA expression profile data of LSCC were downloaded from the public database. After identifying ferroptosis-related differentially expressed genes (FDGs), we explored the role of these genes through functional enrichment analysis. FDGs with prognostic significance were identified by univariate Cox and least absolute shrinkage and selection operator (LASSO) regression analyses. By calculating the risk score, we constructed a prognostic model. Kaplan-Meier (K-M) analysis, the receiver operating characteristic (ROC) curves, and the nomogram were utilized to investigate this model. Public databases and quantitative real-time polymerase chain reaction (qRT-PCR) were performed to verify the expression of model genes. The model consisting of four FDGs was acknowledged to be a self-determining predictor of prognosis. The K-M survival curves and the ROC curves confirmed the model's predictive ability. The C index (0.805) indicates that the nomogram has a good predictive ability. In vitro studies have confirmed the differential expression of the four FDGs. We identified a novel ferroptosis-related gene signature for predicting prognosis in LSCC.