Regulated Process Of Cell Death Research Articles

Unveiling the susceptibility mechanism of Microcystis to consecutive sub-lethal oxidative stress—Enhancing Oxidation Technology for Cyanobacterial Bloom Control

The use of H2O2 to mitigate cyanobacterial blooms has gained popularity due to its selectivity. Previous research has shown that consecutive low-dose H2O2 are far more effective in suppressing cyanobacteria than a single higher dose, minimizing damage to co-existing organisms in the aquatic ecosystem. However, the underlying mechanism remains unclear. This study aimed to investigate the mechanism underlying this sensitivity by monitoring the progression from oxidative stress to cell death in Microcystis induced by consecutive low doses of H2O2 (3+5mg/L, with an interval time of 4hours). The initial application of H2O2 (3mg/L) resulted in a rapid increase in the transcription of antioxidant genes (gpx, 2-cys prx, trxA and sod) within 1h, and returned to baseline levels within 8h. The addition of a second H2O2 led to a significant increase in glutathione peroxidase (gene and product) and glutathione within 24h. The cell death following consecutive H2O2 stress was classified as regulated cell death (RCD), characterized by the upregulated metacaspase genes, increased caspase-like activity, modulation of the mazEF system, DNA fragmentation, cell vacuolization, and membrane disruption. Interestingly, the RCD process coincided with the fluctuation of glutathione cycle. Validation experiments demonstrated that exogenous glutathione can promote the gene expression and activity of metacaspase, while inhibition of glutathione biosynthesis led to decreased intracellular glutathione and suppressed metacaspase activity and gene expression. Therefore, glutathione may play a vital role in the connection between oxidative stress and RCD during consecutive H2O2 treatment. These results reveal the inherent vulnerability of Microcystis to consecutive oxidative stress, providing a biological mechanism for a sustainable strategy to mitigate cyanobacterial bloom.

A Systems Biology Approach Towards a Comprehensive Understanding of Ferroptosis.

Ferroptosis is a regulated cell death process characterized by iron ion catalysis and reactive oxygen species, leading to lipid peroxidation. This mechanism plays a crucial role in age-related diseases, including cancer and cardiovascular and neurological disorders. To better mimic iron-induced cell death, predict the effects of various elements, and identify drugs capable of regulating ferroptosis, it is essential to develop precise models of this process. Such drugs can be tested on cellular models. Systems biology offers a powerful approach to studying biological processes through modeling, which involves accumulating and analyzing comprehensive research data. Once a model is created, it allows for examining the system's response to various stimuli. Our goal is to develop a modular framework for ferroptosis, enabling the prediction and screening of compounds with geroprotective and antiferroptotic effects. For modeling and analysis, we utilized BioUML (Biological Universal Modeling Language), which supports key standards in systems biology, modular and visual modeling, rapid simulation, parameter estimation, and a variety of numerical methods. This combination fulfills the requirements for modeling complex biological systems. The integrated modular model was validated on diverse datasets, including original experimental data. This framework encompasses essential molecular genetic processes such as the Fenton reaction, iron metabolism, lipid synthesis, and the antioxidant system. We identified structural relationships between molecular agents within each module and compared them to our proposed system for regulating the initiation and progression of ferroptosis. Our research highlights that no current models comprehensively cover all regulatory mechanisms of ferroptosis. By integrating data on ferroptosis modules into an integrated modular model, we can enhance our understanding of its mechanisms and assist in the discovery of new treatment targets for age-related diseases. A computational model of ferroptosis was developed based on a modular modeling approach and included 73 differential equations and 93 species.

A lipid droplet-targeting fluorescence probe for monitoring of lipid peroxidation in ferroptosis and non-alcoholic fatty liver disease

Ferroptosis is a new regulated cell death process executed by lipid peroxidation (LPO) of polyunsaturated fatty acids. Lipid droplets (LDs), as an important organelle for lipid storage and metabolism, are probably a major site of LPO and play critical roles in the regulation of ferroptosis. However, the detailed study on LPO in LDs has not been carried out because of the lack of LD-targeting tools for the in situ monitoring of LPO. Herein, the first LD-targeting LPO fluorescence probe (LD-LPO) has been developed. LD-LPO exhibits a rapid and selective fluorescence enhancement at 518 nm, which is unaffected by highly destructive reactive oxygen species (e.g., hydroxyl radical) and environmental factor changes (e.g., polarity and viscosity). LD-LPO is capable of targeting LDs and visualizing LPO within LDs in situ during erastin- or (1S,3R)-RSL3 (RSL3)-induced ferroptosis. Moreover, LD-LPO has also been used to image LPO in the ferroptosis-associated non-alcoholic fatty liver disease (NAFLD), and to evaluate the medicine treatment of NAFLD with saroglitazar, demonstrating its utility for monitoring LPO levels in biosystems. The favorable analytical and imaging performance of LD-LPO may allow its application in more ferroptosis-associated physiological and pathological processes.

Serum apolipoprotein H determines ferroptosis resistance by modulating cellular lipid composition

Ferroptosis is a regulated cell death process dependent on iron, triggered by the accumulation of lipid peroxidation. The environmental context significantly impacts cellular sensitivities to ferroptosis. Serum, constituting the extracellular fluid composition in vivo, provides crucial environmental biomolecules. In this study, we investigated the influence of sera on ferroptosis induction, pinpointing the serum protein apolipoprotein H (APOH) as a pivotal inhibitor of ferroptosis. Moreover, we elucidated that APOH suppresses ferroptosis by activating the phosphoinositide 3-kinase (PI3K)-AKT-sterol regulatory element-binding proteins (SREBPs) pathway, thereby elevating stearoyl-CoA desaturase (SCD) levels and augmenting cellular monounsaturated fatty acid-containing phospholipids (MUFA-PLs). Furthermore, ApoHinfer, the peptide derivative of the active region of APOH, mimics its ferroptosis inhibitory activity. Our findings underscore the critical role of serum protein APOH in the inhibition of ferroptosis and indicates potential therapeutic applications in treating cancer and diseases associated with ferroptosis.

Targeting ferroptosis for improved radiotherapy outcomes in HPV‐negative head and neck squamous cell carcinoma

To enhance the efficacy of radiotherapy (RT) in human papillomavirus (HPV)‐negative head and neck squamous cell carcinoma (HNSCC), we explored targeting ferroptosis, a regulated cell death process. We developed a gene signature associated with ferroptosis using Cox proportional hazard modeling in HPV‐negative HNSCC patients who underwent RT. This ferroptosis‐related gene signature (FRGS) was a significant predictor of overall survival and recurrence‐free survival in HPV‐negative HNSCC patients who received RT. Subtype B of the FRGS, characterized by decreased expression of ferroptosis inducers [nuclear receptor coactivator 4 (NCOA4) and natural resistance‐associated macrophage protein 2 homolog/divalent metal transporter 1 (NRAMP2/DMT1)] and increased expression of suppressors [phospholipid hydroperoxide glutathione peroxidase (GPX4) and ferritin heavy chain (FTH1)], was associated with poorer prognosis, potentially indicating the inhibition of ferroptosis. Furthermore, our in vitro and in vivo studies demonstrated that treatment with statins, such as atorvastatin and simvastatin, induced ferroptosis and sensitized radioresistant HNSCC cells to irradiation, improving radiosensitivity and potentially enhancing the response to RT. Additionally, in xenograft models, the combination of statins and RT led to a significant reduction in tumor initiation. These findings provide valuable insights for enhancing treatment and improving prognosis in HPV‐negative HNSCC by targeting ferroptosis and utilizing statins to sensitize tumors to RT‐induced cell death.

Cell death in bryophytes: emerging models to study core regulatory modules and conserved pathways.

This review summarizes recent progress in our current understanding of the mechanisms underlying the cell death pathways in bryophytes, focusing on conserved pathways and particularities in comparison to angiosperms. Regulated cell death (RCD) plays key roles during essential processes along the plant life cycle. It is part of specific developmental programmes and maintains homeostasis of the organism in response to unfavourable environments. Bryophytes could provide valuable models to study developmental RCD processes as well as those triggered by biotic and abiotic stresses. Some pathways analogous to those present in angiosperms occur in the gametophytic haploid generation of bryophytes, allowing direct genetic studies. In this review, we focus on such RCD programmes, identifying core conserved mechanisms and raising new key questions to analyse RCD from an evolutionary perspective.

EGFR inhibits TNF-α-mediated pathway by phosphorylating TNFR1 at tyrosine 360 and 401

Tumour necrosis factor receptor 1 (TNFR1) induces the nuclear factor kappa-B (NF-κB) signalling pathway and regulated cell death processes when TNF-α ligates with it. Although mechanisms regulating the downstream pathways of TNFR1 have been elucidated, the direct regulation of TNFR1 itself is not well known. In this study, we showed that the kinase domain of the epidermal growth factor receptor (EGFR) regulates NF-κB signalling and TNF-α-induced cell death by directly phosphorylating TNFR1 at Tyr 360 and 401 in its death domain. In contrast, EGFR inhibition by EGFR inhibitors, such as erlotinib and gefitinib, prevented their interaction. Once TNFR1 is phosphorylated, its death domain induces the suppression of the NF-κB pathways, complex II-mediated apoptosis, or necrosome-dependent necroptosis. Physiologically, in mouse models, EGF treatment mitigates TNF-α-dependent necroptotic skin inflammation induced by treatment with IAP and caspase inhibitors. Our study revealed a novel role for EGFR in directly regulating TNF-α-related pathways.

Novel Insights into the Links between N6-Methyladenosine and Regulated Cell Death in Musculoskeletal Diseases.

Musculoskeletal diseases (MSDs), including osteoarthritis (OA), osteosarcoma (OS), multiple myeloma (MM), intervertebral disc degeneration (IDD), osteoporosis (OP), and rheumatoid arthritis (RA), present noteworthy obstacles associated with pain, disability, and impaired quality of life on a global scale. In recent years, it has become increasingly apparent that N6-methyladenosine (m6A) is a key regulator in the expression of genes in a multitude of biological processes. m6A is composed of 0.1-0.4% adenylate residues, especially at the beginning of 3'-UTR near the translation stop codon. The m6A regulator can be classified into three types, namely the "writer", "reader", and "eraser". Studies have shown that the epigenetic modulation of m6A influences mRNA processing, nuclear export, translation, and splicing. Regulated cell death (RCD) is the autonomous and orderly death of cells under genetic control to maintain the stability of the internal environment. Moreover, distorted RCDs are widely used to influence the course of various diseases and receiving increasing attention from researchers. In the past few years, increasing evidence has indicated that m6A can regulate gene expression and thus influence different RCD processes, which has a central role in the etiology and evolution of MSDs. The RCDs currently confirmed to be associated with m6A are autophagy-dependent cell death, apoptosis, necroptosis, pyroptosis, ferroptosis, immunogenic cell death, NETotic cell death and oxeiptosis. The m6A-RCD axis can regulate the inflammatory response in chondrocytes and the invasive and migratory of MM cells to bone remodeling capacity, thereby influencing the development of MSDs. This review gives a complete overview of the regulatory functions on the m6A-RCD axis across muscle, bone, and cartilage. In addition, we also discuss recent advances in the control of RCD by m6A-targeted factors and explore the clinical application prospects of therapies targeting the m6A-RCD in MSD prevention and treatment. These may provide new ideas and directions for understanding the pathophysiological mechanism of MSDs and the clinical prevention and treatment of these diseases.

Ginsenoside Rg5 inhibits glioblastoma by activating ferroptosis via NR3C1/HSPB1/NCOA4

BackgroundThe utilization of Chinese medicine as an adjunctive therapy for cancer has recently gained significant attention. Ferroptosis, a newly regulated cell death process depending on the ferrous ions, has been proved to be participated in glioma stem cells inactivation. PurposeWe aim to study whether ginsenoside Rg5 exerted inhibitory effects on crucial aspects of glioma stem cells, including cell viability, tumor initiation, invasion, self-renewal ability, neurosphere formation, and stemness. MethodsThrough comprehensive sequencing analysis, we identified a compelling association between ginsenoside Rg5 and the ferroptosis pathway, which was further validated through subsequent experiments demonstrating its ability to activate this pathway. ResultsTo elucidate the precise molecular targets affected by ginsenoside Rg5 in gliomas, we conducted an intersection analysis between differentially expressed genes obtained from sequencing and a database-predicted list of transcription factors and potential targets of ginsenoside Rg5. This rigorous approach led us to unequivocally confirm NR3C1 (Nuclear Receptor Subfamily 3 Group C Member 1) as a direct target of ginsenoside Rg5, a finding consistently supported by subsequent experimental investigations. Moreover, we uncovered NR3C1′s capacity to transcriptionally regulate ferroptosis -related genes HSPB1 and NCOA4. Strikingly, ginsenoside Rg5 induced notable alterations in the expression levels of both HSPB1 (Heat Shock Protein Family B Member 1) and NCOA4 (Nuclear Receptor Coactivator 4). Finally, our intracranial xenograft assays served to reaffirm the inhibitory effect of ginsenoside Rg5 on the malignant progression of glioblastoma. ConclusionThese collective findings strongly suggest that ginsenoside Rg5 hampers glioblastoma progression by activating ferroptosis through NR3C1, which subsequently modulates HSPB1 and NCOA4. Importantly, this novel therapeutic direction holds promise for advancing the treatment of glioblastoma.

Abstract 5996: Genome-wide CRISPR screening reveals a central role for ferroptotic cell death in the anti-tumor response to mTOR inhibitors in HNSCC

Abstract Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer globally, resulting in more than 300,000 deaths each year worldwide. Treatment options for HNSCC patients include surgery, radiation, chemotherapy and molecularly targeted therapies, and although immunotherapies have recently revolutionized the treatment landscape, <20% of HNSCC patients respond to immune check point blockade (ICB) therapies. The survival rate of HNSCC patients has changed only modestly over the past decades, and therefore HNSCC is a significant global health problem with high mortality and morbidity. Genomic alterations converging in the persistent activation of the PI3K/mTOR pathway (>80% cases) represent one of the most frequently altered signaling circuitries in HNSCC. This overreliance on PI3K/mTOR signaling for tumor growth may expose a cancer vulnerability that can be exploited therapeutically, as revealed in recent clinical trials using mTOR inhibitors (mTORi) in HNSCC in the adjuvant and neoadjuvant setting. Here, we took advantage of a whole-genome CRISPR screening approach to identify mechanisms of sensitivity and resistance to mTORi, aimed at increasing their clinical activity. We found that the activation of autophagy, a biological process that plays a paradoxical pro-survival or antitumoral role in a cancer specific fashion, is strictly required for mTORi cell growth inhibition in HNSCC. In depth analysis of our CRISPR screening also revealed multiple hits suggestive of a novel role for iron metabolism and ferroptosis downstream from mTORi. Ferroptosis is iron-dependent regulated cell death process caused by the peroxidation of polyunsaturated fatty acids. Indeed, we found that mTORi induces ferroptosis in HNSCC cells, and that inhibition of ferroptosis reduces the effect of mTORi. Evidence will be presented supporting a novel mechanism linking mTORi-triggered autophagy and the activation of ferroptotic death programs, as well as new synergistic combinations with mTORi by repurposing approved drugs that disable cellular ferroptotic defense mechanisms. Our studies uncovered how mTORi act in HNSCC, thereby revealing new multimodal precision therapies for HNSCC and many human malignancies displaying overactive PI3K/mTOR signaling. Citation Format: Keiichi Koshizuka, Xingyu Wu, Kuniaki Sato, Pham Thuy Vo, Gosia M. Murawska, Tomohiko Ishikawa, Zhiyong Wang, Alfredo A. Molinolo, Edward A. Dennis, Prashant Mali, J. Silvio Gutkind. Genome-wide CRISPR screening reveals a central role for ferroptotic cell death in the anti-tumor response to mTOR inhibitors in HNSCC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5996.

Advances in Ferroptosis-Inducing Agents by Targeted Delivery System in Cancer Therapy.

Currently, cancer remains one of the most significant threats to human health. Treatment of most cancers remains challenging, despite the implementation of diverse therapies in clinical practice. In recent years, research on the mechanism of ferroptosis has presented novel perspectives for cancer treatment. Ferroptosis is a regulated cell death process caused by lipid peroxidation of membrane unsaturated fatty acids catalyzed by iron ions. The rapid development of bio-nanotechnology has generated considerable interest in exploiting iron-induced cell death as a new therapeutic target against cancer. This article provides a comprehensive overview of recent advancements at the intersection of iron-induced cell death and bionanotechnology. In this respect, the mechanism of iron-induced cell death and its relation to cancer are summarized. Furthermore, the feasibility of a nano-drug delivery system based on iron-induced cell death for cancer treatment is introduced and analyzed. Secondly, strategies for inducing iron-induced cell death using nanodrug delivery technology are discussed, including promoting Fenton reactions, inhibiting glutathione peroxidase 4, reducing low glutathione levels, and inhibiting system Xc-. Additionally, the article explores the potential of combined treatment strategies involving iron-induced cell death and bionanotechnology. Finally, the application prospects and challenges of iron-induced nanoagents for cancer treatment are discussed.

Regulated Cell Death in Endometriosis.

Regulated cell death (RCD) represents a distinct mode of cell demise, differing from accidental cell death (ACD), characterized by specific signaling cascades orchestrated by diverse biomolecules. The regular process of cell death plays a crucial role in upholding internal homeostasis, acting as a safeguard against biological or chemical damage. Nonetheless, specific programmed cell deaths have the potential to activate an immune-inflammatory response, potentially contributing to diseases by enlisting immune cells and releasing pro-inflammatory factors. Endometriosis, a prevalent gynecological ailment, remains incompletely understood despite substantial progress in unraveling associated signaling pathways. Its complexity is intricately tied to the dysregulation of inflammatory immune responses, with various RCD processes such as apoptosis, autophagic cell death, pyroptosis, and ferroptosis implicated in its development. Notably, limited research explores the association between endometriosis and specific RCD pathways like pyroptosis and cuproptosis. The exploration of regulated cell death in the context of endometriosis holds tremendous potential for further advancements. This article thoroughly reviews the molecular mechanisms governed by regulated cell death and their implications for endometriosis. A comprehensive understanding of the regulated cell death mechanism in endometriosis has the potential to catalyze the development of promising therapeutic strategies and chart the course for future research directions in the field.

Glycyrrhizin attenuates myocardial ischemia reperfusion injury by suppressing Inflammation, oxidative stress, and ferroptosis via the HMGB1-TLR4-GPX4 pathway

Ferroptosis, a form of regulated cell death process, play an important role in myocardial ischemia‒reperfusion (I/R) injury. Glycyrrhizin (GL), a natural glycoconjugate triterpene, has the property to improve growth rate, immune regulation, antioxidant, anti-inflammatory. However, whether GL can attenuate myocardial I/R injury by modulating ferroptosis or other mechanisms are still unclear. In this study, SD rats underwent in vivo myocardial ischemia/reperfusion (I/R) surgery, while H9C2 cells were subjected to the hypoxia/reoxygenation (H/R) model for in vitro experiments. In addition, TAK-242, a TLR4-specific antagonist, and GL were also used to evaluate the effect and mechanisms of GL on the cardiac function and expression of ferroptosis-related gene and protein in vivo and vitro. The results show that GL decreased not only the expression of the inflammation-related factors (HMGB1, TNF-α, IL-6, IL-18 and IL-1β), but also reduced the number of TUNEL-positive cardiomyocytes, and mitigated pathological alterations in I/R injury. In addition, GL decreased the levels of MDA, promoted antioxidant capacity such as GSH, CAT, Cu/Zn-SOD, Mn-SOD, and SOD in vivo and vitro. More importantly, GL and TAK-242 regulate ferroptosis-related protein and gene expression in I/R and H/R model. Surprisingly, GL may ameliorate cardiomyocyte ferroptosis and ultimately improves cardiac function induced by H/R via the HMGB1-TLR4-GPX4 axis. Therefore, we have highlighted a novel mechanism by which GL regulates inflammation, oxidative stress, and ferroptosis via the HMGB1-TLR4-GPX4 pathway to prevent myocardial I/R injury. GL appears to be a potentially applicable drug for the treatment of myocardial I/R injury.

Potential therapies for HCC involving targeting the ferroptosis pathway.

Liver cancer ranks as the third leading cause of cancer-related mortality worldwide, predominantly in the form of hepatocellular carcinoma (HCC). Conventional detection and treatment approaches have proven inadequate for addressing the elevated incidence and mortality rates associated with HCC. However, a significant body of research suggests that combating HCC through the induction of ferroptosis is possible. Ferroptosis is a regulated cell death process characterized by elevated levels of reactive oxygen species (ROS) and lipid peroxide accumulation, both of which are dependent on iron levels. In recent years, there has been an increasing focus on investigating ferroptosis, revealing its potential as an inhibitory mechanism against various diseases, including tumors. Therefore, ferroptosis induction holds great promise for treating multiple types of cancers, including HCC. This article provides a review of the key mechanisms involved in ferroptosis and explores the potential application of multiple targets and pathways associated with ferroptosis in HCC treatment to improve therapeutic outcomes.

Effective prognostic risk model with cuproptosis-related genes in laryngeal cancer

ObjectiveLaryngeal cancer, characterized by high recurrence rates and a lack of effective biomarkers, has been associated with cuproptosis, a regulated cell death process linked to cancer progression. In this study, we aimed to explore the roles of cuproptosis-related genes in laryngeal cancer and their potential as prognostic markers and therapeutic targets. MethodsWe collected comprehensive data from The Cancer Genome Atlas and Gene Expression Omnibus databases, including gene expression profiles and clinical data of laryngeal cancer patients. Using clustering and gene analysis, we identified cuproptosis-related genes with prognostic significance. A risk model was constructed based on these genes, categorizing patients into high- and low-risk groups for outcome comparison. Univariate and multivariate analyses were conducted to identify independent prognostic factors, which were then incorporated into a nomogram. Gene Set Enrichment Analysis was employed to explore pathways distinguishing high- and low-risk groups. ResultsOur risk model, based on four genes, including transmembrane 2, dishevelled binding antagonist of β-catenin 1, stathmin 2, and G protein-coupled receptor 173, revealed significant differences in patient outcomes between high- and low-risk groups. Independent prognostic factors were identified and integrated into a nomogram, providing a valuable tool for prognostic prediction. Gene Set Enrichment Analysis uncovered up-regulated pathways specifically associated with high-risk patient samples. ConclusionThis study highlights the potential of cuproptosis-related genes as valuable prognostic markers and promising therapeutic targets in the context of laryngeal cancer. This research sheds light on new avenues for understanding and managing this challenging disease. Level of evidenceLevel 4.

YTHDC1 as a tumor progression suppressor through modulating FSP1-dependent ferroptosis suppression in lung cancer.

Ferroptosis is a regulated cell death process initiated by iron-dependent phospholipid peroxidation and is mainly suppressed by GPX4-dependent and FSP1-dependent surveillance mechanisms. However, how the ferroptosis surveillance system is regulated during cancer development remains largely unknown. Here, we report that the YTHDC1-mediated m6A epigenetic regulation of FSP1 alleviates the FSP1-dependent ferroptosis suppression that partially contributes to the tumor suppressive role of YTHDC1 in lung cancer progression. YTHDC1 knockdown promoted the lung tumor progression and upregulated FSP1 protein level that resulted in ferroptosis resistance of lung cancer cells. Silencing FSP1 abrogated YTHDC1 knockdown-induced proliferation increase and ferroptosis resistance. Mechanistically, YTHDC1 binding to the m6A sites in the FSP1 3'-UTR recruited the alternative polyadenylation regulator CSTF3 to generate a less stable shorter 3'-UTR contained FSP1 mRNA, whereas YTHDC1 downregulation generated the longer 3'-UTR contained FSP1 mRNA that is stabilized by RNA binding protein HuR and thus led to the enhanced FSP1 protein level. Therefore, our findings identify YTHDC1 as a tumor progression suppressor in lung cancer and a ferroptosis regulator through modulating the FSP1 mRNA stability and thus suggest a ferroptosis-related therapeutic option for YTHDC1high lung cancer.

Comprehensive analysis of ICD-related lncRNAs in predicting risk stratification, clinical prognosis and immune response for breast cancer.

Breast cancer (BRCA) represents a significant threat with high mortality rates due to relapse, metastasis, and chemotherapy resistance. As a regulated cell death process characterized by the induction of immunogenic signals, immunogenic cell death (ICD) has been identified as an effective anti-tumorigenesis approach. However, the comprehensive study and its clinical value of ICD-related lncRNAs in BRCA is still missing. The transcriptome matrix and corresponding clinical information of BRCA patients were obtained from The Cancer Genome Atlas (TCGA) database. Pearson correlation analysis was performed to identify ICD-related lncRNAs (ICDRLs). To determine the prognostic value of the identified ICDRLs, univariate Cox regression analysis, LASSO algorithm, and multivariate Cox regression analysis were employed to construct a risk model. The prognostic risk model was subsequently evaluated using univariate and multivariate Cox regression analysis, as well as Nomogram analysis. In vitro experiments were also conducted to validate the bioinformatics findings using quantitative real-time PCR (qRT-PCR). We established a prognostic risk signature consisting of five ICDRLs. The prognostic value of this model was subsequently confirmed in guiding BRCA prognostic stratification. Furthermore, we explored the correlation of the risk score with various clinical characteristics and chemotherapy response. qRT-PCR result confirmed the abnormal expression of ICDRLs, which was consistent with the bioinformatics data. Our findings provide evidence of the critical role of ICDRLs in BRCA and offer a novel perspective for exploring precise treatment options for BRCA patients.

Single-cell sequencing and bulk RNA data reveal the tumor microenvironment infiltration characteristics of disulfidptosis related genes in breast cancer.

Immunotherapy, represented by immune checkpoint inhibitors, has made significant progress in the treatment of cancer. Numerous studies have demonstrated that antitumor therapies targeting cell death exhibit synergistic effects with immunotherapy. Disulfidptosis is a recently discovered form of cell death, and its potential influence on immunotherapy, similar to other regulated cell death processes, requires further investigation. The prognostic value of disulfidptosis in breast cancer and its role in the immune microenvironment has not been investigated. High dimensional weighted gene coexpression network analysis (hdWGCNA) and Weighted co-expression network analysis (WGCNA) methods were employed to integrate breast cancer single-cell sequencing data and bulk RNA data. These analyses aimed to identify genes associated with disulfidptosis in breast cancer. Risk assessment signature was constructed using Univariate Cox and least absolute shrinkage and selection operator (LASSO) analyses. In this study, we constructed a risk signature by disulfidptosis-related genes to predict overall survival and immunotherapy response in BRCA patients. The risk signature demonstrated robust prognostic power and accurately predicted survival compared to traditional clinicopathological features. It also effectively predicted the response to immunotherapy in patients with breast cancer. Through cell communication analysis in additional single-cell sequencing data, we identified TNFRSF14 as a key regulatory gene. Combining TNFRSF14 targeting and immune checkpoint inhibition to induce disulfidptosis in tumor cells could potentially suppress tumor proliferation and enhance survival in patients with BRCA.

Combination of transcriptomic, proteomic and degradomic profiling reveals common and distinct patterns of pathogen-induced cell death in maize.

Regulated cell death (RCD) is crucial for plant development, as well as in decision-making in plant-microbe interactions. Previous studies revealed components of the molecular network controlling RCD, including different proteases. However, the identity, the proteolytic network as well as molecular components involved in the initiation and execution of distinct plant RCD processes, still remain largely elusive. In this study, we analyzed the transcriptome, proteome and N-terminome of Zea mays leaves treated with the Xanthomonas effector avrRxo1, the mycotoxin Fumonisin B1 (FB1), or the phytohormone salicylic acid (SA) to dissect plant cellular processes related to cell death and plant immunity. We found highly distinct and time-dependent biological processes being activated on transcriptional and proteome levels in response to avrRxo1, FB1 and SA. A correlation analysis of the transcriptome and proteome identified general, as well as trigger-specific markers for cell death in Z. mays. We found that proteases, particularly papain-like cysteine proteases, are specifically regulated during RCD. Collectivley, this study characterizes distinct RCD responses in Z. mays and provides a framework for the mechanistic exploration of components involved in the initiation and execution of cell death.

Hydrogen sulfide alleviates beryllium sulfate-induced ferroptosis and ferritinophagy in 16HBE cells.

Beryllium sulfate (BeSO4 ) can result to lung injuries, such as leading to lipid peroxidation and autophagy, and the treatment of beryllium disease has not been well improved. Ferroptosis is a regulated cell death process driven by iron-dependent and lipid peroxidation, while ferritinophagy is a process mediated by nuclear receptor coactivator 4 (NCOA4), combined with ferritin heavy chain 1 (FTH1) degradation and release Fe2+ , which regulated intracellular iron metabolism and ferroptosis. Hydrogen sulfide (H2 S) has the effects of antioxidant, antiautophagy, and antiferroptosis. This study aimed to investigate the effect of H2 S on BeSO4 -induced ferroptosis and ferritinophagy in 16HBE cells and the underlying mechanism. In this study, BeSO4 -induced 16HBE cell injury model was established based on cellular level and pretreated with deferoxamine (DFO, a ferroptosis inhibitor), sodium hydrosulfide (NaHS, a H2 S donor), or NCOA4 siRNA and, subsequently, performed to detect the levels of lipid peroxidation and Fe2+ and the biomarkers of ferroptosis and ferritinophagy. More importantly, our research found that DFO, NaHS, or NCOA4 siRNA alleviated BeSO4 -induced ferroptosis and ferritinophagy by decreasing the accumulation of Fe2+ and lipid peroxides. Furthermore, the relationship between ferroptosis, ferritinophagy, H2 S, and beryllium disease is not well defined; therefore, our research is innovative. Overall, our results provided a new theoretical basis for the prevention and treatment of beryllium disease and suggested that the application of H2 S, blocking ferroptosis, and ferritinophagy may be a potential therapeutic direction for the prevention and treatment of beryllium disease.