Mechanisms Regulating Cell Death Research Articles

Epigallocatechin gallate modulates ferroptosis through downregulation of tsRNA-13502 in non-small cell lung cancer

Ferroptosis, an iron-dependent regulated cell death mechanism, holds significant promise as a therapeutic strategy in oncology. In the current study, we explored the regulatory effects of epigallocatechin gallate (EGCG), a prominent polyphenol in green tea, on ferroptosis and its potential therapeutic implications for non-small cell lung cancer (NSCLC). Treatment of NSCLC cell lines with varying concentrations of EGCG resulted in a notable suppression of cell proliferation, as evidenced by a reduction in Ki67 immunofluorescence staining. Western blot analyses demonstrated that EGCG treatment led to a decrease in the expression of glutathione peroxidase 4 (GPX4) and solute carrier family 7 member 11 (SLC7A11) while increasing the levels of acyl-CoA synthetase long-chain family member 4 (ACSL4). These molecular changes were accompanied by an increase in intracellular iron, malondialdehyde (MDA), and reactive oxygen species (ROS), alongside ultrastructural alterations characteristic of ferroptosis. Through small RNA sequencing and RT-qPCR, transfer RNA-derived small RNA 13502 (tsRNA-13502) was identified as a significant target of EGCG action, with its expression being upregulated in NSCLC tissues compared to adjacent non-tumorous tissues. EGCG was found to modulate the ferroptosis pathway by downregulating tsRNA-13502 and altering the expression of key ferroptosis regulators (GPX4/SLC7A11 and ACSL4), thereby promoting the accumulation of iron, MDA, and ROS, and ultimately inducing ferroptosis in NSCLC cells. This study elucidates EGCG’s multifaceted mechanisms of action, underscoring the modulation of ferroptosis as a viable therapeutic approach for enhancing NSCLC treatment outcomes.

A multi-platform analysis of human gingival crevicular fluid reveals ferroptosis as a relevant regulated cell death mechanism during the clinical progression of periodontitis.

Ferroptosis is implicated in the pathogenesis of numerous chronic-inflammatory diseases, yet its association with progressive periodontitis remains unexplored. To investigate the involvement and significance of ferroptosis in periodontitis progression, we assessed sixteen periodontitis-diagnosed patients. Disease progression was clinically monitored over twelve weeks via weekly clinical evaluations and gingival crevicular fluid (GCF) collection was performed for further analyses. Clinical metrics, proteomic data, in silico methods, and bioinformatics tools were combined to identify protein profiles linked to periodontitis progression and to explore their potential connection with ferroptosis. Subsequent western blot analyses validated key findings. Finally, a single-cell RNA sequencing (scRNA-seq) dataset (GSE164241) for gingival tissues was analyzed to elucidate cellular dynamics during periodontitis progression. Periodontitis progression was identified as occurring at a faster rate than traditionally thought. GCF samples from progressing and non-progressing periodontal sites showed quantitative and qualitatively distinct proteomic profiles. In addition, specific biological processes and molecular functions during progressive periodontitis were revealed and a set of hub proteins, including SNCA, CA1, HBB, SLC4A1, and ANK1 was strongly associated with the clinical progression status of periodontitis. Moreover, we found specific proteins - drivers or suppressors - associated with ferroptosis (SNCA, FTH1, HSPB1, CD44, and GCLC), revealing the co-occurrence of this specific type of regulated cell death during the clinical progression of periodontitis. Additionally, the integration of quantitative proteomic data with scRNA-seq analysis suggested the susceptibility of fibroblasts to ferroptosis. Our analyses reveal proteins and processes linked to ferroptosis for the first time in periodontal patients, which offer new insights into the molecular mechanisms of progressive periodontal disease. These findings may lead to novel diagnostic and therapeutic strategies.

Abstract 360: Dissecting the role of oncogenic KRAS and ferroptosis within colorectal cancer

Abstract Introduction: Ferroptosis is a novel iron-dependent regulated cell death mechanism triggered by a toxic accumulation of membrane lipid peroxidation. This mechanism is counteracted by ferroptosis defense systems, such as the GPX4/GSH system, which function as antioxidants that limit lipid peroxidation. Oncogenic KRAS (KRASmut) is a key driver for many aggressive cancers, including colorectal cancer (CRC). Previous studies have suggested that oncogenic KRAS plays a pleiotropic role in the ferroptosis pathway. Yet, the interplay between oncogenic KRAS and ferroptosis has not been fully elucidated in CRC. Here, we aimed to dissect the role of oncogenic KRAS in ferroptosis using CRC as a cancer model. Methods: Cells from a KRAS-inducible model (iKAP) were seeded and treated with ferroptosis-inducing drugs (e.g., Erastin and RSL3) and/or a KRAS inhibitor (MRTX1133). Lipid peroxidation was then measured by BODIPY assay followed by flow cytometry to detect the quantity of BODIPY-stained cells. Protein expression of known ferroptosis defense mechanisms was also profiled (e.g., SLC7A11 [xCT] and GPX4). Results: Results from this study demonstrate that KRASmut activation leads to a reduction in mean fluorescence intensity when compared to KRASWT of BODIPY-stained cells. This decreased mean fluorescence intensity is indicative of lower levels of lipid peroxidation and, consequently, ferroptosis. KRASmut cells were also found to be resistant to ferroptosis following treatment with ferroptosis inducers. To replicate a pharmacologically induced KRASWT phenotype, iKAP cells were treated with MRTX1133, which led to a significant decrease in viability when combined with RSL3. We observed a decreased protein expression of the membrane antiporter xCT following treatment with MRTX1133, which we believe works synergistically with the GPX4 inhibition of RSL3. Conclusion: We observed that KRASmut may induce resistance to ferroptosis in vitro in CRC cells. Genetic and pharmacological inhibition of KRAS resulted in sensitization to ferroptosis inducers. Future work will uncover mechanisms through which oncogenic KRAS leads to ferroptosis resistance in CRC. More importantly, understanding the interaction between ferroptosis, oncogenic KRAS, and its antagonist systems has significant therapeutic potential in oncology. Citation Format: Alexandra Rosa-Vázquez, Vincent Bernard-Pagan, Jasper Chen, Cullen Taniguchi. Dissecting the role of oncogenic KRAS and ferroptosis within colorectal cancer [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 360.

Induction of ferroptosis by natural phenols: A promising strategy for cancer therapy.

In recent years, heightened interest surrounds the exploration of natural phenols as potential agents for cancer therapy, specifically by inducing ferroptosis, a unique form of regulated cell death characterized by iron-dependent lipid peroxidation. This review delves into the roles of key natural phenols, flavonoids, phenolic acids, curcumin, and stilbenes, in modulating ferroptosis and their underlying mechanisms. Emphasizing the significance of amino acid, lipid, and iron metabolism, the study elucidates the diverse pathways through which these phenols regulate ferroptosis. Notably, curcumin, a well-known polyphenol, exhibits multifaceted interactions with cellular components involved in ferroptosis regulation, providing a distinctive therapeutic avenue. Stilbenes, another phenolic class, demonstrate promising potential in influencing lipid metabolism and iron-dependent processes, contributing to ferroptotic cell death. Understanding the intricate interplay between these natural phenols and ferroptosis not only illuminates complex cellular regulatory networks but also unveils potential avenues for novel cancer therapies. Exploring these compounds as inducers of ferroptosis presents a promising strategy for targeted cancer treatment, capitalizing on the delicate balance between cellular metabolism and regulated cell death mechanisms. This article synthesizes current knowledge, aiming to stimulate further research into the therapeutic potential of natural phenols in the context of ferroptosis-mediated cancer therapy.

Emerging Therapeutic Approaches Targeting Ferroptosis in Cancer: Focus on Immunotherapy and Nanotechnology.

Ferroptosis is a newly discovered form of programmed cell death characterized by iron overload, ROS accumulation, and lipid peroxidation. It is distinguished by unique morphological, biochemical, and genetic features and stands apart from other known regulated cell death mechanisms. Studies have demonstrated a close association between ferroptosis and various cancers, including liver cancer, lung cancer, renal cell carcinoma, colorectal cancer, pancreatic cancer, and ovarian cancer. Inducing ferroptosis has shown promising results in inhibiting tumor growth and reversing tumor progression. However, the challenge lies in regulating ferroptosis in vivo due to the scarcity of potent compounds that can activate it. Integrating emerging biomedical discoveries and technological innovations with conventional therapies is imperative. Notably, considerable progress has been made in cancer treatment by leveraging immunotherapy and nanotechnology to trigger ferroptosis. This review explores the relationship between ferroptosis and emerging immunotherapies and nanotechnologies, along with their potential underlying mechanisms, offering valuable insights for developing novel cancer treatment strategies.

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.

Focus on the Function and Mechanism of Pyroptosis in Rheumatoid Arthritis

The most important and basic processe that occurs inside of cells is cell death. There are several regulated cell death mechanisms, such as pyroptosis, necroptosis and apoptosis. Distinct sets of host proteins that contribute to biological outcomes regulate all such activities. Caspases regulate the execution of processes like pyroptosis and apoptosis. Inflammatory caspases trigger the process of pyroptosis, which results in necrotic, inflammatory cell death that causes inflammatory illness, even though it acts as a defense mechanism against a variety of microorganisms. The autoimmune, chronic inflammatory illness named as ''rheumatoid arthritis (RA)''is characterized by inflammation in the joints caused by inflammatory- promoting cytokines such as tumor necrosis factor-alpha and interleukin-6. Rheumatoid arthritis is mainly characterized by synovitis, which is followed by clinical manifestation like stiffness, pain, swelling in several joints, malaise and fever as well as involvement of organ that are extra-articular like, interstitial pneumonia. Soon after the outset, joint damage advances, and once the impacted joints are distorted, irreversible physical impairment starts to manifest. Clarifying the role of pyroptosis in RA was the main goal of this review.

Iron Dyshomeostasis and Mitochondrial Function in the Failing Heart: A Review of the Literature.

Cardiac contraction and relaxation require a substantial amount of energy provided by the mitochondria. The failing heart is adenosine triphosphate (ATP)- and creatine-depleted. Studies have found iron is involved in almost every aspect of mitochondrial function, and previous studies have shown myocardial iron deficiency in heart failure (HF). Many clinicians advocated intravenous iron repletion for HF patients meeting the conventional criteria for systemic iron deficiency. While clinical trials showed improved quality of life, iron repletion failed to significantly impact survival or significant cardiovascular adverse events. There is evidence that in HF, labile iron is trapped inside the mitochondria causing oxidative stress and lipid peroxidation. There is also compelling preclinical evidence demonstrating the detrimental effects of both iron overload and depletion on cardiomyocyte function. We reviewed the mechanisms governing myocardial and mitochondrial iron content. Mitochondrial dynamics (i.e., fusion, fission, mitophagy) and the role of iron were also investigated. Ferroptosis, as an important regulated cell death mechanism involved in cardiomyocyte loss, was reviewed along with agents used to manipulate it. The membrane stability and iron content of mitochondria can be altered by many agents. Some studies are showing promising improvement in the cardiomyocyte function after iron chelation by deferiprone; however, whether the in vitro and in vivo findings will be reflected on on clinical grounds is still unclear. Finally, we briefly reviewed the clinical trials on intravenous iron repletion. There is a need for more well-simulated animal studies to shed light on the safety and efficacy of chelation agents and pave the road for clinical studies.

MELK promotes HCC carcinogenesis through modulating cuproptosis-related gene DLAT-mediated mitochondrial function

Cuproptosis caused by copper overload is mediated by a novel regulatory mechanism that differs from previously documented mechanisms regulating cell death. Cells dependent on mitochondrial respiration showed increased sensitivity to a copper ionophore elesclomol that induced cuproptosis. Maternal embryonic leucine zipper kinase(MELK) promotes tumorigenesis and tumor progression through the PI3K/mTOR pathway, which exerts its effects partly by targeting the pyruvate dehydrogenase complex(PDHc) and reprogramming the morphology and function of mitochondria. However, the role of MELK in cuproptosis remains unclear. Here, we validated that elevated MELK expression enhanced the activity of PI3K/mTOR signaling and subsequently promoted Dihydrolipoamide S-Acetyltransferase (DLAT) expression and stabilized mitochondrial function. This regulatory effect helped to improve mitochondrial respiration, eliminate excessive intracellular reactive oxygen species (ROS), reduce intracellular oxidative stress/damage and the possibility of mitochondria-induced cell fate alternations, and ultimately promote the progression of HCC. Meanwhile, elesclomol reduced translocase of outer mitochondrial membrane 20(TOM 20) expression and increased DLAT oligomers. Moreover, the above changes of MELK to HCC were abolished by elesclomol. In conclusion, MELK enhanced the levels of the cuproptosis-related signature(CRS) gene DLAT (especially the proportion of DLAT monomer) by activating the PI3K/mTOR pathway, thereby promoting elesclomol drug resistance, altering mitochondrial function, and ultimately promoting HCC progression.

Pazopanib ameliorates rotenone-induced Parkinsonism in rats by suppressing multiple regulated cell death mechanisms

Parkinson’s disease (PD) is characterized by motor impairments and progressive dopaminergic neuronal death in the substantia nigra (SN). Recently, the involvement of other regulated cell death (RCD) machineries has been highlighted in PD. Necroptosis is controlled by p-RIPK1, p-RIPK3, and p-MLKL and negatively regulated by caspase-8. Ferroptosis is characterized by iron overload and accumulation of reactive oxygen species. Interestingly, the molecular chaperone complex HSP90/CDC37 has been reported to directly regulate necroptosis, ferroptosis, and some PD-associated proteins. We investigated the potential anti-necroptotic and anti-ferroptotic effects of the anti-cancer drug pazopanib, uncovering the HSP90/CDC37 complex as a master RCD modulator in rotenone-induced Parkinsonism in rats. Oral administration of 15 mg/kg pazopanib to rotenone-intoxicated rats for three weeks improved motor deficits, debilitated histopathological changes, and increased striatal dopaminergic levels. Pazopanib suppressed LRRK2 and c-Abl. Pazopanib displayed an anti-necroptotic effect through inhibition of the p-RIPK1/p-RIPK3/p-MLKL pathway and activation of caspase-8. Moreover, pazopanib inhibited the ferroptotic p-VEGFR2-PKCβII-PLC-γ-ACSL-4 pathway, iron, 4-HNE, and PTGS2 while increasing GPX-4 and GSH levels. Taken together, the current research sheds light on the repositioning of pazopanib targeting HSP90/CDC37 and its multiple RCD mechanisms, which would offer a new perspective for therapeutic strategies in PD.

Metal-Based Photosensitizers as Inducers of Regulated Cell Death Mechanisms.

Over the last few decades, various forms of regulated cell death (RCD) have been discovered and were found to improve cancer treatment. Although there are several reviews on RCD induced by photodynamic therapy (PDT), a comprehensive summary covering metal-based photosensitizers (PSs) as RCD inducers has not yet been presented. In this review, we systematically summarize the works on metal-based PSs that induce different types of RCD, including ferroptosis, immunogenic cell death (ICD), and pyroptosis. The characteristics and mechanisms of each RCD are explained. At the end of each section, a summary of the reported commonalities between different metal-based PSs inducing the same RCD is emphasized, and future perspectives on metal-based PSs inducing novel forms of RCD are discussed at the end of the review. Considering the essential roles of metal-based PSs and RCD in cancer therapy, we hope that this review will provide the stage for future advances in metal-based PSs as RCD inducers.

Radiotherapy-induced ferroptosis for cancer treatment.

Ferroptosis is a regulated cell death mechanism controlled by iron, amino acid and reactive oxygen species metabolisms, which is very relevant for cancer therapy. Radiotherapy-induced ferroptosis is critical for tumor suppression and several preclinical studies have demonstrated that the combination of ionizing radiation with small molecules or nano-systems is effective in combating cancer growth and overcoming drug or ionizing radiation resistance. Here, we briefly overview the mechanisms of ferroptosis and the cross-talk existing between the cellular pathways activated by ferroptosis and those induced by radiotherapy. Lastly, we discuss the recently reported combinational studies involving radiotherapy, small molecules as well as nano-systems and report the recent findings achieved in this field for the treatment of tumors.

Identification of immunogenic cell death-associated subtypes and characterization of the tumor microenvironment in endometrial cancer.

Immunogenic cell death (ICD) is one of the mechanisms regulating cell death, which activates adaptive immunity in immunocompetent hosts and is associated with tumor progression, prognosis and therapeutic response. Endometrial cancer (EC) is one of the most common malignancies of the female genital tract, and the potential role of immunogenic cell death-related genes (IRGs) in the tumor microenvironment (TME) remains unclear. We describe the variation of IRGs and assess the expression patterns in EC samples from The Cancer Genome Atlas and Gene Expression Omnibus cohorts. Based on the expression of 34 IRGs, we identified two different ICD-related clusters and subsequently differentially expressed genes between the two ICD-related clusters were used for the identification of two ICD gene clusters. We identified the clusters and found that alterations in the multilayer IRG were associated with patient prognosis and TME cell infiltration characteristics. On this basis, ICD score risk scores were calculated, and ICD signatures were constructed and validated for their predictive power in EC patients. To help clinicians better apply the ICD signature, an accurate nomogram was constructed. The low ICD risk group was characterized by high microsatellite instability, high tumor mutational load, high IPS score and stronger immune activation. Our comprehensive analysis of IRGs in EC patients suggested a potential role in the tumor immune interstitial microenvironment, clinicopathological features and prognosis. These findings may improve our understanding of the role of ICDs, and provide a new basis for assessing prognosis and developing more effective immunotherapeutic strategies in EC.

Kinases control of regulated cell death revealing druggable targets for Parkinson's disease.

Parkinson's disease (PD) is the second most prevalent neurodegenerative disorder in the world. Motor impairment seen in PD is associated with dopaminergic neurotoxicity in the striatum, and dopaminergic neuronal death in the substantia nigra pars compacta. Cell death has a significant effect on the development and progression of PD. Extensive research over the last few decades has unveiled new regulated cell death (RCD) mechanisms that are not dependent on apoptosis such as necroptosis, ferroptosis, and others. In this review, we will overview the mechanistic pathways of different types of RCD. Unlike accidental cell death, RCD subroutines can be regulated and the RCD-associated kinases are potential druggable targets. Hence, we will address an overview and analysis of different kinases regulating apoptosis such as receptor-interacting protein kinase 1 (RIPK-1), RIPK3, mixed lineage kinase (MLK), Ataxia telangiectasia muted (ATM), cyclin-dependent kinase (CDK), death-associated protein kinase 1 (DAPK1), Apoptosis-signaling kinase-1 (ASK-1), and Leucine-rich repeat kinase-2 (LRRK2). In addition to the role of RIPK1, RIPK3, and Mixed Lineage Kinase Domain like Pseudokinase (MLKL) in necroptosis. We also overview functions of AMP-kinase (AMPK), protein kinase C (PKC), RIPK3, and ATM in ferroptosis. We will recap the anti-apoptotic, anti-necroptotic, and anti-ferroptotic effects of different kinase inhibitors in different models of PD. Finally, we will discuss future challenges in the repositioning of kinase inhibitors in PD. In conclusion, this review kicks-start targeting RCD from a kinases perspective, opening novel therapeutic disease-modifying therapeutic avenues for PD.

A Cuproptosis-Related lncRNAs Signature Could Accurately Predict Prognosis in Patients with Clear Cell Renal Cell Carcinoma.

Clear cell renal cell carcinoma (ccRCC) is the most common subtype of kidney cancers. As cuproptosis, a new cell death mechanism proposed recently, differs from all other known mechanisms regulating cell death, we aimed to create prognostic markers using cuproptosis-related long non-coding ribonucleic acids (RNAs; lncRNAs) and elucidate the molecular mechanism. Data from transcriptome RNA sequencing of ccRCC samples and the relevant clinical data were downloaded from The Cancer Genome Atlas, and Pearson's correlation analysis was implemented to obtain the cuproptosis-related lncRNAs. Then, univariate Cox, multivariate Cox, and Least Absolute Shrinkage and Selection Operator Cox analyses were performed to construct the risk signatures. The cuproptosis-related lncRNAs predictive signature was evaluated with receiver operating characteristic curves and subgroup analysis. Finally, Gene Set Enrichment Analysis (GSEA), single-sample GSEA (ssGSEA), tumor immune microenvironment (TIME), and immune checkpoints were performed to explore the relationship between immunity and patient prognosis. Five cuproptosis-related lncRNAs, including FOXD2-AS1, LINC00460, AC091212.1, AC007365.1, and AC026401.3, were used to construct the signature. In the training and test sets, low-risk groups (as identified by a risk score lower than the median) demonstrated a better prognosis with an area under the curve for 1-, 3-, and 5-year survival being 0.793, 0.716, and 0.719, respectively. GSEA analysis suggested significant enrichment of the tricarboxylic acid cycle and metabolism-related pathways in the low-risk group. Besides, both ssGSEA and TIME suggested that the high-risk group exhibited more active immune infiltration. We proposed a cuproptosis-related lncRNAs signature, which had the potential for prognoses and prediction. Our findings might contribute to elucidating potential genomic biomarkers and targets for future therapies in the cuproptosis-related signaling pathways.

An Ascovirus Utilizes Different Types of Host Larval Regulated Cell Death Mechanisms To Produce and Release Vesicles.

Ascoviruses are insect-specific viruses that are thought to utilize the cellular apoptotic processes of host larvae to produce numerous virion-containing vesicles. In this study, we monitored the in vivo infection processes of Heliothis virescens ascovirus 3h (HvAV-3h) to illustrate the regulated cell death (RCD) of host cells. Transmission electron microscopic observations did not reveal any morphological markers of apoptosis in the fat bodies or hemocytes of HvAV-3h-infected Helicoverpa armigera or Spodoptera exigua larvae. However, several hemocytes showed the morphological criteria for necrosis and/or pyroptosis. Further in vitro biochemical tests were performed to confirm the RCD type of host cells after infection with HvAV-3h. Different morphological characteristics were found between the early (prior to 24 hours post-infection, [hpi]) and later (48 to 120 hpi) stages in both HvAV-3h infected larval fat bodies and hemocytes. In the early stages, the virions could only be found in several adipohemocytes, and the fat bodies were cleaving their contained lipid inclusions into small lipid dots. In the later stage, both fat bodies and hemocytes were filled with numerous virions. According to the morphological characteristics of HvAV-3h infected larval fat bodies or hemocytes, the pathogenic characteristics and infection patterns of HvAV-3h in the host larvae were described, and the systematic pathogenic mode of ascovirus infection was refined in this study. This study details the complete infection process of ascoviruses, which provides insights into the relationship between a pathogenesis of an insect virus and the RCD of different host tissues at different stages of infection. IMPORTANCE Viruses and other pathogens can interrupt host cellular apoptosis to gain benefits, such as sufficient resources and a stable environment that enables them to complete their replication and assembly. It is unusual for viruses to code proteins with homology to caspases, which are commonly recognized as apoptosis regulators. Ascoviruses are insect viruses with special cytopathology, and they have been hypothesized to induce apoptosis in their host larvae via coding a caspase-like protein. This enables them to utilize the process of cellular apoptosis to facilitate vesicle formation and replication. However, our previous studies revealed different trends. The fat bodies and hemocytes of Heliothis virescens ascovirus 3h (HvAV-3h)-infected larvae did not show any morphological markers of apoptosis but did display necrosis and/or pyroptosis morphological characteristics. The pathogenic characteristics and infection patterns of HvAV-3h in the host larvae were described, which can help us understand the relationship between the pathogenesis of an insect virus and host RCD.

High expression of cuproptosis-related gene FDX1 in relation to good prognosis and immune cells infiltration in colon adenocarcinoma (COAD)

BackgroundCuproptosis induced by FDX1 is a newly discovered mechanism regulating cell death. However, the role of FDX1 in the pathogenesis of colon adenocarcinoma (COAD) remains to be studied.MethodsFDX1 expression was analyzed with The Cancer Genome Atlas (TCGA) database and Human Protein Atlas (HPA) database. Association between FDX1 expression and COAD prognosis was investigated via the Kaplan–Meier (KM) survival curve. The differentially expressed genes (DEGs) of FDX1 were screened with R packages and the PPI were constructed via STRING database. Cytoscape software was used to detect the most profound modules in the PPIs network. CancerSEA database was used to analyze the effect of FDX1 expression levels on different functional status of COAD cells. The relationship between FDX1 expression and immune infiltration of COAD was analyzed by TIMER2.0 database. The COAD patients with high expression of FDX1 by Western blot, and the levels of immune infiltration were measured by flow cytometry.ResultsFDX1 was low expressed in most cancers, such as BRCA, KICH, and COAD. The overall survival (OS) and disease-specific survival (DSS) of COAD with high FDX1 expression were better than that of the low expression group. GO-KEGG enrichment analysis revealed that FDX1 and its co-expressed genes played an important role in the pathogenesis of COAD. Moreover, FDX1 expression in COAD were positively associated with “quiescence” and “inflammation” but negatively correlated with “invasion”. FDX1 expression was positively correlated with infiltration levels of CD8+ T cells, NK cells, and neutrophils. Oppositely, FDX1 expression was negatively correlated with that of CD4+ T cells and cancer-associated fibroblasts (CAFs). Finally, 6 COAD patients with high expression of FDX1 were screened, and the proportion of CD8+ T cells in cancer tissues of these patients was significantly higher than that in paracancerous, while the CD4+ T cells presented the opposite pattern.ConclusionFDX1 plays a role in inducing cuproptosis and modulating tumor immunity, which could be considered as potential therapeutic targets in COAD.

Ferroptosis Inducers for Prostate Cancer Therapy.

Lipid peroxidation-driven iron-dependent ferroptosis is a regulated cell death mechanism implicated in numerous diseases, such as neurological diseases, kidney injury, ischemia, and tumors, including prostate cancer. The cellular mechanisms of ferroptosis are strongly associated with iron, reactive oxygen species and amino acid metabolic pathways. Several compounds, namely ferroptosis inducers, impact these pathways and trigger ferroptosis by i) inhibiting Xc - transporter system, ii) impairing GPX4 functions and iii) oxidizing iron and polyunsaturated phospholipids. Preclinical studies show that in combination with conventional anticancer drugs, ferroptosis inducers are effective in prostate cancer and in combating the progression towards the castration-resistant disease. This review overviews the mechanisms implicated in ferroptosis and discusses the findings achieved in prostate cancer.

Revisiting Regulated Cell Death Responses in Viral Infections.

The fate of a viral infection in the host begins with various types of cellular responses, such as abortive, productive, latent, and destructive infections. Apoptosis, necroptosis, and pyroptosis are the three major types of regulated cell death mechanisms that play critical roles in viral infection response. Cell shrinkage, nuclear condensation, bleb formation, and retained membrane integrity are all signs of osmotic imbalance-driven cytoplasmic swelling and early membrane damage in necroptosis and pyroptosis. Caspase-driven apoptotic cell demise is considered in many circumstances as an anti-inflammatory, and some pathogens hijack the cell death signaling routes to initiate a targeted attack against the host. In this review, the selected mechanisms by which viruses interfere with cell death were discussed in-depth and were illustrated by compiling the general principles and cellular signaling mechanisms of virus–host-specific molecule interactions.

Ferroptosis promotes T-cell activation-induced neurodegeneration in multiple sclerosis.

While many drugs are effective at reducing the relapse frequency of multiple sclerosis (MS), there is an unmet need for treatments that slow neurodegeneration resulting from secondary disease progression. The mechanism of neurodegeneration in MS has not yet been established. Here, we discovered a potential pathogenetic role of ferroptosis, an iron-dependent regulated cell death mechanism, in MS. We found that critical ferroptosis proteins (acyl-CoA synthetase long-chain family member 4, ACSL4) were altered in an existing genomic database of MS patients, and biochemical features of ferroptosis, including lipid reactive oxygen species (ROS) accumulation and mitochondrial shrinkage, were observed in the experimental autoimmune encephalitis (EAE) mouse model. Targeting ferroptosis with ferroptosis inhibitors or reducing ACSL4 expression improved the behavioral phenotypes of EAE mice, reduced neuroinflammation, and prevented neuronal death. We found that ferroptosis was an early event in EAE, which may promote T-cell activation through T-cell receptor (TCR) signaling in vitro and in vivo. These data indicate that ferroptosis may be a potential target for treating MS.