Advances in understanding the role of lncRNA in ferroptosis.

LncRNA is a type of transcript with a length exceeding 200 nucleotides, which was once considered junk transcript with no biological function during the transcription process. In recent years, lncRNA has been shown to act as an important regulatory factor at multiple levels of gene expression, affecting various programmed cell death modes including ferroptosis. Ferroptosis, as a new form of programmed cell death, is characterized by a deficiency of cysteine or inactivation of glutathione peroxidase, leading to depletion of glutathione, aggregation of iron ions, and lipid peroxidation. These processes are influenced by many physiological processes, such as the Nrf2 pathway, autophagy, p53 pathway and so on. An increasing number of studies have shown that lncRNA can block the expression of specific molecules through decoy effect, guide specific proteins to function, or promote interactions between molecules as scaffolds. These modes of action regulate the expression of key factors in iron metabolism, lipid metabolism, and antioxidant metabolism through epigenetic or genetic regulation, thereby regulating the process of ferroptosis. In this review, we snapshotted the regulatory mechanism of ferroptosis as an example, emphasizing the regulation of lncRNA on these pathways, thereby helping to fully understand the evolution of ferroptosis in cell fate.

Modifiable risk factors, oxidative stress markers, and SOD2 rs4880 SNP in coronary artery disease: an association study.

BACKGROUND: Coronary artery disease (CAD) has been linked to single nucleotide polymorphism (SNP) in superoxide dismutase 2 (SOD 2) gene. Additionally, several modifiable risk factors are also known to influence the CAD risk. AIM: To investigate the association between selected modifiable risk factors and oxidative stress markers with the SOD2 rs4880 SNP in CAD patients. METHODS: A cohort of 150 angiographically confirmed CAD patients, and 100 control subjects in the same geographic area were enrolled. SOD levels and lipid peroxidation were assessed in the blood samples using standard protocols. The genotyping of the SOD2 gene was conducted through the PCR-sequencing method. RESULTS: This study indicated that CAD patients with the rs4880 SNP having heterozygous AG and mutated homozygous GG genotypes have increased oxidative stress, decreased SOD activity, and a positive association with CAD risk (OR 2.85) in comparison with control individuals. The investigation among CAD patients was then carried out based on modifiable risk factors. The risk factors selected were clinical characteristics, physical habits, nutritional status, and body mass index. In all the cases, MDA levels showed a positive association, and SOD activity showed a negative association with the selected polymorphism. CONCLUSIONS: The study suggests that the selected modifiable risk factors have an important role in the higher oxidative stress found in patients, which may lead to SOD2 polymorphism. It also suggests that the SOD2 locus can be identified as a marker gene for CAD susceptibility.

Oxidative Stress Biomarkers in Male Infertility: Established Methodologies and Future Perspectives.

Male fertility can be affected by oxidative stress (OS), which occurs when an imbalance between the production of reactive oxygen species (ROS) and the body's ability to neutralize them arises. OS can damage cells and influence sperm production. High levels of lipid peroxidation have been linked to reduced sperm motility and decreased fertilization ability. This literature review discusses the most commonly used biomarkers to measure sperm damage caused by ROS, such as the high level of OS in seminal plasma as an indicator of imbalance in antioxidant activity. The investigated biomarkers include 8-hydroxy-2-deoxyguanosine acid (8-OHdG), a marker of DNA damage caused by ROS, and F2 isoprostanoids (8-isoprostanes) produced by lipid peroxidation. Furthermore, this review focuses on recent methodologies including the NGS polymorphisms and differentially expressed gene (DEG) analysis, as well as the epigenetic mechanisms linked to ROS during spermatogenesis along with new methodologies developed to evaluate OS biomarkers. Finally, this review addresses a valuable insight into the mechanisms of male infertility provided by these advances and how they have led to new treatment possibilities. Overall, the use of biomarkers to evaluate OS in male infertility has supplied innovative diagnostic and therapeutic approaches, enhancing our understanding of male infertility mechanisms.

Tau Aggregation-Dependent Lipid Peroxide Accumulation Driven by the hsa_circ_0001546/14-3-3/CAMK2D/Tau Complex Inhibits Epithelial Ovarian Cancer Peritoneal Metastasis.

Intraperitoneal dissemination is the main method of epithelial ovarian cancer (EOC) metastasis, which is related to poor prognosis and a high recurrence rate. Circular RNAs (circRNAs) are a novel class of endogenous RNAs with covalently closed loop structures that are implicated in the regulation of tumor development. In this study, hsa_circ_0001546 is downregulated in EOC primary and metastatic tissues vs. control tissues and this phenotype has a favorable effect on EOC OS and DFS. hsa_circ_0001546 can directly bind with 14-3-3 proteins to act as a chaperone molecule and has a limited positive effect on 14-3-3 protein stability. This complex recruits CAMK2D to induce the Ser324 phosphorylation of Tau proteins, changing the phosphorylation status of Tau bound to 14-3-3 and ultimately forming the hsa_circ_0001546/14-3-3/CAMK2D/Tau complex. The existence of this complex stimulates the production of Tau aggregation, which then induces the accumulation of lipid peroxides (LPOs) and causes LPO-dependent ferroptosis. In vivo, treatment with ferrostatin-1 and TRx0237 rescued the inhibitory effect of hsa_circ_0001546 on EOC cell spreading. Therefore, based on this results, ferroptosis caused by Tau aggregation occurs in EOC cells, which is not only in Alzheimer's disease- or Parkinson's disease-related cells and this kind of ferroptosis driven by the hsa_circ_0001546/14-3-3/CAMK2D/Tau complex is LPO-dependent rather than GPX4-dependent is hypothesized.

Microbial-transcriptome integrative analysis of heat stress effects on amino acid metabolism and lipid peroxidation in poultry jejunum.

Despite the significant threat of heat stress to livestock animals, only a few studies have considered the potential relationship between broiler chickens and their microbiota. Therefore, this study examined microbial modifications, transcriptional changes and host-microbiome interactions using a predicted metabolome data-based approach to understand the impact of heat stress on poultry. After the analysis, the host functional enrichment analysis revealed that pathways related to lipid and protein metabolism were elevated under heat stress conditions. In contrast, pathways related to the cell cycle were suppressed under normal environmental temperatures. In line with the transcriptome analysis, the microbial analysis results indicate that taxonomic changes affect lipid degradation. Heat stress engendered statistically significant difference in the abundance of 11 microorganisms, including Bacteroides and Peptostreptococcacea. Together, integrative approach analysis suggests that microbiota-induced metabolites affect host fatty acid peroxidation metabolism, which is correlated with the gene families of Acyl-CoA dehydrogenase long chain (ACADL), Acyl-CoA Oxidase (ACOX) and Acetyl-CoA Acyltransferase (ACAA). This integrated approach provides novel insights into heat stress problems and identifies potential biomarkers associated with heat stress.

Striking a NRF2: The Rusty and Rancid Vulnerabilities Toward Ferroptosis in Alzheimer's Disease.

Significance: The lack of disease-modifying treatments for Alzheimer's disease (AD) that substantially alter the course of the disease highlights the need for new biological models of disease progression and neurodegeneration. Oxidation of macromolecules within the brain, including lipids, proteins, and DNA, is believed to contribute to AD pathophysiology, concomitant with dysregulation of redox-active metals, such as iron. Creating a unified model of pathogenesis and progression underpinned by iron dysregulation and redox dysregulation in AD could lead to new therapeutic targets with disease-modifying potential. Recent Advances: Ferroptosis, which was named in 2012, is a necrotic form of regulated cell death that depends on both iron and lipid peroxidation. While it is distinct from other types of regulated cell death, ferroptosis is regarded as being mechanistically synonymous with oxytosis. The ferroptosis paradigm has great explanatory potential in describing how neurons degenerate and die in AD. At the molecular level, ferroptosis is executed by the lethal accumulation of phospholipid hydroperoxides generated by the iron-dependent peroxidation of polyunsaturated fatty acids, while the major defensive protein against ferroptosis is the selenoenzyme, glutathione peroxidase 4 (GPX4). An expanding network of protective proteins and pathways have also been identified to complement GPX4 in the protection of cells against ferroptosis, with a central role emerging for nuclear factor erythroid 2-related factor 2 (NRF2). Critical Issues: In this review, we provide a critical overview of the utility of ferroptosis and NRF2 dysfunction in understanding the iron- and lipid peroxide-associated neurodegeneration of AD. Future Directions: Finally, we discuss how the ferroptosis paradigm in AD is providing a new spectrum of therapeutic targets. Antioxid. Redox Signal. 39, 141-161.

A ferroptosis defense mechanism mediated by glycerol-3-phosphate dehydrogenase 2 in mitochondria.

Mechanisms of defense against ferroptosis (an iron-dependent form of cell death induced by lipid peroxidation) in cellular organelles remain poorly understood, hindering our ability to target ferroptosis in disease treatment. In this study, metabolomic analyses revealed that treatment of cancer cells with glutathione peroxidase 4 (GPX4) inhibitors results in intracellular glycerol-3-phosphate (G3P) depletion. We further showed that supplementation of cancer cells with G3P attenuates ferroptosis induced by GPX4 inhibitors in a G3P dehydrogenase 2 (GPD2)-dependent manner; GPD2 deletion sensitizes cancer cells to GPX4 inhibition-induced mitochondrial lipid peroxidation and ferroptosis, and combined deletion of GPX4 and GPD2 synergistically suppresses tumor growth by inducing ferroptosis in vivo. Mechanistically, inner mitochondrial membrane-localized GPD2 couples G3P oxidation with ubiquinone reduction to ubiquinol, which acts as a radical-trapping antioxidant to suppress ferroptosis in mitochondria. Taken together, these results reveal that GPD2 participates in ferroptosis defense in mitochondria by generating ubiquinol.

Regulated cell death joins in atherosclerotic plaque silent progression.

Non-apoptotic regulated cell death (ferroptosis and necroptosis) leads to the release of damage-associated molecular patterns (DAMPs), which initiate and perpetuate a non-infectious inflammatory response. We hypothesize that DAMPs and non-apoptotic regulated cell death are critical players of atherosclerotic plaque progression with inadequate response to lipid-lowering treatment. We aimed to uncover the silent mechanisms that govern the existing residual risk of cardiovascular-related mortality in experimental atherosclerosis. Proteomic and genomic approaches were applied on the ascending aorta of hyperlipidemic rabbits and controls with and without lipid-lowering treatment. The hyperlipidemic animals, which presented numerous heterogeneous atherosclerotic lesions, exhibited high concentrations of serum lipids and increased lipid peroxidation oxidative stress markers. The analyses revealed the significant upregulation of DAMPs and proteins implicated in ferroptosis and necroptosis by hyperlipidemia. Some of them did not respond to lipid-lowering treatment. Dysregulation of five proteins involved in non-apoptotic regulated cell death proteins (VDAC1, VDAC3, FTL, TF and PCBP1) and nine associated DAMPs (HSP90AA1, HSP90AB1, ANXA1, LGALS3, HSP90B1, S100A11, FN, CALR, H3-3A) was not corrected by the treatment. These proteins could play a key role in the atherosclerotic silent evolution and may possess an unexplored therapeutic potential. Mass spectrometry data are available via ProteomeXchange with identifier PXD026379.

Understanding the role of cysteine in ferroptosis: progress & paradoxes.

Cysteine is a conditionally essential amino acid required for the synthesis of proteins and many important intracellular metabolites. Cysteine depletion can trigger iron-dependent nonapoptotic cell death-ferroptosis. Despite this, cysteine itself is normally maintained at relatively low levels within the cell, and many mechanisms that could act to buffer cysteine depletion do not appear to be especially effective or active, at least in cancer cells. How do we reconcile these seemingly paradoxical features? Here, we describe the regulation of cysteine and its contribution to ferroptosis and speculate about how the levels of this amino acid are controlled to govern nonapoptotic cell death.

SARS-CoV-2 deregulates the vascular and immune functions of brain pericytes via Spike protein.

Coronavirus disease 19 (COVID-19) is a respiratory illness caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). COVID-19 pathogenesis causes vascular-mediated neurological disorders via elusive mechanisms. SARS-CoV-2 infects host cells via the binding of viral Spike (S) protein to transmembrane receptor, angiotensin-converting enzyme 2 (ACE2). Although brain pericytes were recently shown to abundantly express ACE2 at the neurovascular interface, their response to SARS-CoV-2 S protein is still to be elucidated. Using cell-based assays, we found that ACE2 expression in human brain vascular pericytes was increased upon S protein exposure. Pericytes exposed to S protein underwent profound phenotypic changes associated with an elongated and contracted morphology accompanied with an enhanced expression of contractile and myofibrogenic proteins, such as α-smooth muscle actin (α-SMA), fibronectin, collagen I, and neurogenic locus notch homolog protein-3 (NOTCH3). On the functional level, S protein exposure promoted the acquisition of calcium (Ca2+) signature of contractile ensheathing pericytes characterized by highly regular oscillatory Ca2+ fluctuations. Furthermore, S protein induced lipid peroxidation, oxidative and nitrosative stress in pericytes as well as triggered an immune reaction translated by activation of nuclear factor-kappa-B (NF-κB) signaling pathway, which was potentiated by hypoxia, a condition associated with vascular comorbidities that exacerbate COVID-19 pathogenesis. S protein exposure combined to hypoxia enhanced the production of pro-inflammatory cytokines involved in immune cell activation and trafficking, namely macrophage migration inhibitory factor (MIF). Using transgenic mice expressing the human ACE2 that recognizes S protein, we observed that the intranasal infection with SARS-CoV-2 rapidly induced hypoxic/ischemic-like pericyte reactivity in the brain of transgenic mice, accompanied with an increased vascular expression of ACE2. Moreover, we found that SARS-CoV-2 S protein accumulated in the intranasal cavity reached the brain of mice in which the nasal mucosa is deregulated. Collectively, these findings suggest that SARS-CoV-2 S protein impairs the vascular and immune regulatory functions of brain pericytes, which may account for vascular-mediated brain damage. Our study provides a better understanding for the mechanisms underlying cerebrovascular disorders in COVID-19, paving the way to develop new therapeutic interventions.

Construction of a Ferroptosis-Related Nine-lncRNA Signature for Predicting Prognosis and Immune Response in Hepatocellular Carcinoma.

Ferroptosis is an iron-dependent cell death process that plays important regulatory roles in the occurrence and development of cancers, including hepatocellular carcinoma (HCC). Moreover, the molecular events surrounding aberrantly expressed long non-coding RNAs (lncRNAs) that drive HCC initiation and progression have attracted increasing attention. However, research on ferroptosis-related lncRNA prognostic signature in patients with HCC is still lacking. In this study, the association between differentially expressed lncRNAs and ferroptosis-related genes, in 374 HCC and 50 normal hepatic samples obtained from The Cancer Genome Atlas (TCGA), was evaluated using Pearson's test, thereby identifying 24 ferroptosis-related differentially expressed lncRNAs. The least absolute shrinkage and selection operator (LASSO) algorithm and Cox regression model were used to construct and validate a prognostic risk score model from both TCGA training dataset and GEO testing dataset (GSE40144). A nine-lncRNA-based signature (CTD-2033A16.3, CTD-2116N20.1, CTD-2510F5.4, DDX11-AS1, LINC00942, LINC01224, LINC01231, LINC01508, and ZFPM2-AS1) was identified as the ferroptosis-related prognostic model for HCC, independent of multiple clinicopathological parameters. In addition, the HCC patients were divided into high-risk and low-risk groups according to the nine-lncRNA prognostic signature. The gene set enrichment analysis enrichment analysis revealed that the lncRNA-based signature might regulate the HCC immune microenvironment by interfering with tumor necrosis factor α/nuclear factor kappa-B, interleukin 2/signal transducers and activators of transcription 5, and cytokine/cytokine receptor signaling pathways. The infiltrating immune cell subtypes, such as resting memory CD4(+) T cells, follicular helper T cells, regulatory T cells, and M0 macrophages, were all significantly different between the high-risk group and the low-risk group as indicated in Spearman's correlation analysis. Moreover, a substantial increase in the expression of B7H3 immune checkpoint molecule was found in the high-risk group. Our findings provided a promising insight into ferroptosis-related lncRNAs in HCC and a personalized prediction tool for prognosis and immune responses in patients.

TRP Channels as Sensors of Aldehyde and Oxidative Stress.

The transient receptor potential (TRP) cation channel superfamily comprises more than 50 channels that play crucial roles in physiological processes. TRP channels are responsive to several exogenous and endogenous biomolecules, with aldehydes emerging as a TRP channel trigger contributing to a cellular cascade that can lead to disease pathophysiology. The body is not only exposed to exogenous aldehydes via tobacco products or alcoholic beverages, but also to endogenous aldehydes triggered by lipid peroxidation. In response to lipid peroxidation from inflammation or organ injury, polyunsaturated fatty acids undergo lipid peroxidation to aldehydes, such as 4-hydroxynonenal. Reactive aldehydes activate TRP channels via aldehyde-induced protein adducts, leading to the release of pro-inflammatory mediators driving the pathophysiology caused by cellular injury, including inflammatory pain and organ reperfusion injury. Recent studies have outlined how aldehyde dehydrogenase 2 protects against aldehyde toxicity through the clearance of toxic aldehydes, indicating that targeting the endogenous aldehyde metabolism may represent a novel treatment strategy. An addition approach can involve targeting specific TRP channel regions to limit the triggering of a cellular cascade induced by aldehydes. In this review, we provide a comprehensive summary of aldehydes, TRP channels, and their interactions, as well as their role in pathological conditions and the different therapeutical treatment options.

SLC7A11/ xCT is a target of miR-5096 and its restoration partially rescues miR-5096-mediated ferroptosis and anti-tumor effects in human breast cancer cells.

Breast cancer cells evade cell death by overexpressing SLC7A11, which functions by transporting cystine into cells in exchange for intracellular glutamate facilitating glutathione synthesis and reducing reactive oxygen species (ROS)-mediated stress. Using an in silico approach, we predicted an miRNA (miR-5096) that can target and downregulate SLC7A11. We demonstrated SLC7A11 as a target of miR-5096 by 3'UTR luciferase assay and further validated it by identifying reduced mRNA and protein levels of SLC7A11 upon miR-5096 overexpression. miR-5096-induced ferroptotic cell death in human breast cancer cells was confirmed by concurrently increased ROS, OH-, lipid ROS, and iron accumulation levels and decreased GSH and mitochondrial membrane potential (MitoTracker™ Orange) with mitochondrial shrinkage and partial cristae loss (observed by TEM). miR-5096 inhibited colony formation, transwell migration, and breast cancer cell invasion, whereas antimiR-5096 promoted these tumorigenic properties. Ectopic expression of SLC7A11 partly reversed miR-5096-mediated effects on cell survival, ROS, lipid peroxides, iron accumulation, GSH, hydroxyl radicals, mitochondrial membrane potential, and colony formation. miR-5096 modulated the expression of epithelial-mesenchymal transition markers in vitro and inhibited the metastatic potential of MDA-MB-231 cells in a tumor xenograft model of zebrafish larvae. Our results demonstrate that miR-5096 is a tumor-suppressive miRNA in breast cancer cells, and this paper discusses its therapeutic implications.

Interleukin-6 promotes ferroptosis in bronchial epithelial cells by inducing reactive oxygen species-dependent lipid peroxidation and disrupting iron homeostasis.

Asthma occurs accompanied by the ferroptosis in bronchial epithelial cells, during which Interleukin-6 (IL-6) plays a key role. However, the associations between IL-6, ferroptosis and asthma have not been reported. Bronchial epithelial cells BEAS-2B cells were induced by different concentrations of IL-6 and cell viability was detected by MTT assay. The TBARS production rate was detected by corresponding kit. The expression of oxidative stress-related indexes was detected by ELISA. The Iron Assay Kits detected total iron levels and ferrous ion (Fe2+) levels. Labile iron pool assay was used to detect the cell unstable iron pool. The expression of ferroptosis-related proteins was detected by Western blot. To further examine the mechanism of action, ferroptosis inhibitor Ferrostatin 1 (Fer-1), antioxidant NAC, and the iron supplement Fe were added. We found that IL-6 decreased the activity, promoted lipid peroxidation, disrupted iron homeostasis of BEAS-2B cells, and induced iron death in bronchial epithelial BEAS-2B cells. However, pretreatment with Ferrostatin-1 (Fer-1) and antioxidant NAC partially reversed the effect of IL-6 on lipid peroxidation and ferroptosis in BEAS-2B cells, while Fe augmented the effect. Overall, IL-6 promotes ferroptosis in bronchial epithelial cells by inducing reactive oxygen species (ROS)-dependent lipid peroxidation and disrupting iron homeostasis.

Effects of Lipid Peroxidation-Mediated Ferroptosis on Severe Acute Pancreatitis-Induced Intestinal Barrier Injury and Bacterial Translocation.

Ferroptosis is a recently recognized type of regulated cell death characterized by iron- and lipid peroxidation-mediated nonapoptotic cell death. However, whether ferroptosis is involved in severe acute pancreatitis- (SAP-) induced intestinal barrier injury is unknown. The aim of this study was to investigate whether ferroptosis is involved in SAP-induced intestinal barrier injury, particularly intestinal epithelial cell (IEC) death, and determine whether the inhibition of ferroptosis would ameliorate intestinal barrier injury and prevent bacterial translocation (BT). Sodium taurocholate (5%) was retrogradely perfused into the biliopancreatic duct to establish a rat model of SAP. The rats were divided into three groups: sham operation (SO), SAP-induced intestinal barrier injury (SAP), and ferroptosis inhibitor liproxstatin-1 (SAP + Lip). Serum indexes were measured in the rats. In addition, the biochemical and morphological changes associated with ferroptosis were observed, including iron accumulation in intestinal tissue, lipid peroxidation levels, and mitochondrial shrinkage. Hematoxylin staining and eosin staining were used to assess histological tissue changes. Western blot, RT-PCR, and immunofluorescent staining were performed to analyze the expression of ferroptosis-related proteins and genes as well as tight junction. BT was detected by 16S rDNA sequencing analysis. The results indicated that ferroptosis was significantly induced in the IECs from rats with SAP and ferroptosis was mediated by lipid peroxidation. The specific lipid peroxidation of IECs clearly upregulated ferroptosis and exacerbated intestinal barrier injury. Furthermore, treatment with liproxstatin-1 lowered the levels of serum damage markers, decreased lipid peroxidation, and alleviated intestinal and acute remote organ injury in SAP rats. In addition, inhibition of ferroptosis reduced BT. Our findings are the first to demonstrate that ferroptosis contributes to SAP-induced intestinal barrier injury via lipid peroxidation-mediated IEC death. These results suggest that ferroptosis is a potential therapeutic target for SAP-induced intestinal barrier injury.

Salusin­ß participates in high glucose­induced HK­2 cell ferroptosis in a Nrf­2­dependent manner.

Ferroptosis is critically involved in the pathophysiology of diabetic nephropathy (DN). As a bioactive peptide, salusin­ß is abundantly expressed in the kidneys. However, it is unclear whether salusin­ß participates in the pathologies of diabetic kidney damage by regulating ferroptosis. The present study found that high glucose (HG) treatment upregulated the protein expressions of salusin­ß in a dose­ and time­dependent manner. Genetic knockdown of salusin­ß retarded, whereas overexpression of salusin­ß aggravated, HG­triggered iron overload, antioxidant capability reduction, massive reactive oxygen species production and lipid peroxidation in HK­2 cells. Mechanistically, salusin­ß inactivated nuclear factor erythroid­derived 2­like 2 (Nrf­2) signaling, thus contributing to HG­induced ferroptosis­related changes in HK­2 cells. Notably, the protein expression of salusin­ß was upregulated by ferroptosis activators, such as erastin, RSL3, FIN56 and buthionine sulfoximine. Pretreatment with ferrostatin­1 (a ferroptosis inhibitor) prevented the upregulated protein expression of salusin­ß in HK­2 cells exposed to HG. Taken together, these results suggested that a positive feedback loop between salusin­ß and ferroptosis primes renal tubular cells for injury in diabetes.

CREB stimulates GPX4 transcription to inhibit ferroptosis in lung adenocarcinoma.

Ferroptosis is a new form of regulated cell death and closely related to cancer. However, the mechanism underlying the regulation of ferroptosis in lung adenocarcinoma (LUAD) remains unclear. IB, IHC and ELISA were performed to analyze protein expression. RT­qPCR was used to analyze mRNA expression. Cell viability, 3D cell growth, MDA, the generation of lipid ROS and the Fe2+ concentration were measured to evaluate the responses to the induction of ferroptosis. Measurement of luciferase activity and ChIP were used to analyze the promoter activity regulated by the transcriptional regulator. Co­IP assays were performed to identify protein­protein interactions. In the present study, it was revealed that cAMP response element­binding protein (CREB) was highly expressed in LUAD, and knockdown of CREB inhibited cell viability and growth by promoting apoptosis­ and ferroptosis­like cell death, concurrently. It was observed that CREB suppressed lipid peroxidation by binding the promoter region of glutathione peroxidase 4 (GPX4), and this binding could be enhanced by E1A binding protein P300 (EP300). The bZIP domain in CREB and the CBP/p300­HAT domain in EP300 were essential for CREB­EP300 binding in LUAD cells. Finally, it was revealed that CREB, GPX4, EP300 and 4­HNE were closely related to tumor size and stage, and tumors with a higher degree of malignancy were more likely to have a low degree of lipid peroxidation. Therefore, targeting this CREB/EP300/GPX4 axis may provide new strategies for treating LUAD.

Comparative transcriptome analyses revealed different heat stress responses in pigeonpea (Cajanus cajan) and its crop wild relatives.

KEY MESSAGE: Comparative transcriptome analyses accompanied by biochemical assays revealed high variability in heat stress response in Cajanus species. Among the studied species, C. scarabaeoides was the most thermotolerant followed by C. cajanifolius, C. cajan, and C. acutifolius. Pigeonpea is one of the climate-resilient grain legumes. Though the optimum temperature for cultivated pigeonpea is ~ 25-35 °C, its wild relatives grow in temperatures ranging between 18 and 45 °C. To gain insight into molecular mechanisms responsible for the heat stress tolerance in pigeonpea, we conducted time-series transcriptome analysis of one pigeonpea cultivar (Cajanus cajan) and two wild relatives, Cajanus acutifolius, and Cajanus scarabaeoides subjected to heat stress at 42 ± 2 ºC for 30 min and 3 h. A total of 9521, 12,447, and 5282 identified transcripts were differentially expressed in C. cajan, C. acutifolius, and C. scarabaeoides, respectively. In this study, we observed that a significant number of genes undergo alternative splicing in a species-specific pattern during heat stress. Gene expression profiling analysis, histochemical assay, chlorophyll content, and electrolyte leakage assay showed that C. scarabaeoides has adaptive features for heat stress tolerance. The gene set enrichment analyses of differentially expressed genes in these Cajanus species during heat stress revealed that oxidoreductase activity, transcription factor activity, oxygen-evolving complex, photosystem-II, thylakoid, phenylpropanoid biosynthetic process, secondary metabolic process, and flavonoid biosynthetic process were highly affected. The histochemical assay showed more lipid peroxidation in C. acutifolius compared to other Cajanus species inferring the presence of higher quantities of polyunsaturated fatty acids in the plasma membrane which might have led to severe damage of membrane-bound organelles like chloroplast, and high electrolyte leakage during heat stress. This study paves the way for the identification of candidate genes, which can be useful for the development of thermo-tolerant pigeonpea cultivars.

Dimethyl fumarate induces ferroptosis and impairs NF-κB/STAT3 signaling in DLBCL.

Despite the development of novel targeted drugs, the molecular heterogeneity of diffuse large B-cell lymphoma (DLBCL) still poses a substantial therapeutic challenge. DLBCL can be classified into at least 2 major subtypes (germinal center B cell [GCB]-like and activated B cell [ABC]-like DLBCL), each characterized by specific gene expression profiles and mutation patterns. Here we demonstrate a broad antitumor effect of dimethyl fumarate (DMF) on both DLBCL subtypes, which is mediated by the induction of ferroptosis, a form of cell death driven by the peroxidation of phospholipids. As a result of the high expression of arachidonate 5-lipoxygenase in concert with low glutathione and glutathione peroxidase 4 levels, DMF induces lipid peroxidation and thus ferroptosis, particularly in GCB DLBCL. In ABC DLBCL cells, which are addicted to NF-κB and STAT3 survival signaling, DMF treatment efficiently inhibits the activity of the IKK complex and Janus kinases. Interestingly, the BCL-2-specific BH3 mimetic ABT-199 and an inhibitor of ferroptosis suppressor protein 1 synergize with DMF in inducing cell death in DLBCL. Collectively, our findings identify the clinically approved drug DMF as a promising novel therapeutic option in the treatment of both GCB and ABC DLBCLs.