Hydrogen polysulfide (H2Sn, n > 1), as an active sulfur substance derived from hydrogen sulfide, is considered a new potential signaling molecule that occupies an irreplaceable position in physiological regulation and signal transduction processes. Ferroptosis, an iron-dependent form of programmed cell death, is caused by the iron dependent accumulation of lipid peroxides associated with reactive oxygen species. The process of ferroptosis generates abundant reactive oxygen species, indirectly promoting the elevation of intracellular hydrogen polysulfide levels. There is evidence to suggest a close relationship between ferroptosis and arthritis. This work developed a near-infrared ratiometric fluorescent probe (Mito-S4) with a large Stokes shift (∼240 nm) based on nucleophilic addition mechanism, which can quickly (18 s) and sensitively (Detection Limit = 0.165 μM) detect H2Sn in cells. The mechanism of action was verified through theoretical calculations and nuclear magnetic analysis, and the probe Mito-S4 was successfully applied to visualize H2Sn in cellular mitochondria. The cell imaging results showed that the probe successfully achieved tracking of H2Sn in mitochondria during inflammation and ferroptosis processes. In addition, pathological section experiments have confirmed that the probe has good in vivo imaging ability. It is worth mentioning that further in vivo imaging experiments have for the first time delved into the mechanism of H2Sn in the process of ferroptosis in arthritis, which can provide new research methods and therapeutic targets for the treatment of arthritis.

Esophageal cancer, a highly malignant tumor with poor prognosis, is characterized by the presence of cancer stem cells (CSCs) that drive tumor initiation, metastasis, and recurrence. This study investigates the molecular mechanism by which glucose transporter 1 (GLUT1) maintains esophageal CSC-like properties through regulation of autophagy-dependent ferroptosis via epidermal growth factor receptor (EGFR). Using shRNA to knock down GLUT1 or EGFR and constructing a GLUT1 overexpression vector in KYSE520 cells, we employed western blotting, qRT-PCR, flow cytometry, sphere formation, Transwell assays, and xenograft models to assess stemness markers (NANOG, OCT4, SOX2), autophagic flux (LC3B, P62, Beclin1), and ferroptosis-related parameters (ROS, Fe2+, GSH, GPX4, COX2). Mechanistic analyses included co-immunoprecipitation to validate the GLUT1-EGFR interaction, chloroquine to inhibit autophagy, and cycloheximide/MG132 to evaluate EGFR protein stability. Results showed that GLUT1 depletion reduced CSC marker expression, increased ROS and Fe2+ levels, depleted GSH, and induced lipid peroxidation, sensitizing cells to ferroptosis while activating autophagy (elevated LC3 II/I, Beclin1; reduced P62); autophagy inhibition exacerbated cell death, indicating a protective role for autophagy in this context. GLUT1 directly bound to EGFR, stabilizing the receptor by blocking ubiquitin-proteasome-mediated degradation, whereas EGFR knockdown enhanced autophagic flux and reversed GLUT1-overexpression-induced ferroptosis resistance and stemness maintenance. In vivo, GLUT1 knockdown suppressed tumor growth and lung metastasis, and clinical samples revealed a positive correlation between GLUT1 and EGFR expression, linked to advanced TNM stages and poor survival. Collectively, these findings demonstrate that GLUT1 preserves esophageal CSC-like characteristics by stabilizing EGFR to inhibit autophagy-dependent ferroptosis, highlighting targeting GLUT1 as a potential therapeutic strategy to eliminate CSCs and combat esophageal cancer progression.

Clear-cell renal cell carcinoma (ccRCC) is a highly aggressive malignancy that originates in the kidney. It often exhibits a limited response or can be refractory to a wide range of anti-cancer therapies, including tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors. Ferroptosis is a form of oxidative, iron-dependent cell death characterized by lipid peroxidation. Targeting ferroptosis may offer a promising alternative therapeutic strategy for cancer cells that are resistant to existing treatments. The impact of ferroptosis-related genes on the prognosis of ccRCC patients is still not fully understood. In this study, we identified 30 differentially expressed ferroptosis-related genes in ccRCC samples compared to normal tissues using data from The Cancer Genome Atlas (TCGA). Lasso regression analyses, along with Kaplan-Meier analysis, were conducted to identify genes associated with prognosis. Based on scRNA-seq and spatial transcriptome analysis, we identified specificity of MIOX in ccRCC. Furthermore, MIOX demonstrated the highest significance, highlighting its independent prognostic value as a single gene in ccRCC. Our findings suggest that MIOX could serve as potential targets for therapeutic interventions in ccRCC.

Multiple sclerosis is an inflammatory disease of the central nervous system (CNS), characterized by oligodendrocyte loss and demyelination of axons leading to neurodegeneration and severe neurological disability. Despite the existing drugs that have immunomodulatory effects an adequate therapy that slow down or stop neuronal death has not yet been found. Oxidative stress accompanied by excessive release of iron into the extracellular space, mitochondrial damage and lipid peroxidation are important factors in the controlled cell death named ferroptosis, latterly recognized in MS. As the fullerenols exhibit potent antioxidant activity, recent results imply that they could have protective effects by suppressing ferroptosis. Based on the current knowledge we addressed the main mechanisms of the protective effects of fullerenols in the CNS in relation to ferroptosis. Inhibition of inflammation, iron overload and lipid peroxidation through the signal transduction mechanism of Nuclear Factor Erythroid 2-Related Factor 2 (NRF2), chelation of heavy metals and free radical scavenging using fullerenols are proposed as benefitial strategy preventing MS progression. Current review connects ferroptosis molecular targets and important factors of MS progression, with biomedical properties and mechanisms of fullerenols' actions, to propose new treatment strategies that could be addaptobale in other neurodegenerative diseases.

The vulnerability of tumor cells to lipid peroxidation, driven by redox imbalance and lipid overabundance within the tumor microenvironment (TME), has become a focal point for novel antitumor strategies. Ferroptosis, a form of regulated cell death predicated on lipid peroxidation, is emerging as a promising approach. Beyond their role in directly eliminating tumor cells, lipid peroxidation and its products, such as 4-hydroxynonenal (HNE), exert an additional influence by damaging DNA and shaping an environment conducive to tumor growth and metastasis. This process polarizes macrophages towards a pro-inflammatory phenotype, dampens the antigen-presenting capacity of dendritic cells (DCs), and undermines the cytotoxic functions of T and NK cells. Furthermore, it transforms neutrophils into pro-tumorigenic polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs). The lipid peroxidation of stroma cells also contributes to tumor progression. Although advanced nanotherapies have shown the ability to target tumor cells precisely, they often overlook the nuanced effects of lipid peroxidation products. In this review, we highlight a synergistic mechanism in which lipid peroxidation products and ferroptosis contribute to an immunosuppressive state that is temporally distinct from cell death. This insight broadens our understanding of ferroptosis-derived immunosuppression, encompassing all types of immune cells within the TME. This review aims to catalyze further research in this underexplored area, emphasizing the potential of lipid peroxidation products to hinder the clinical translation of ferroptosis-based therapies.

We aim to construct a RiskScore model to aid in the early prognosis of breast cancer (BC).

BC mRNA expression profiles were obtained from TCGA and GEO databases. Differential gene expression analysis identifies PDP1-ferroptosis-related genes. LASSO Cox regression was utilized to screen genes to build a RiskScore model, and survival analysis were performed to investigate the reliability in BC prognosis. Immune cell infiltration proportions were calculated using CIBERSORT and xCell algorithms. Single-cell data processing and analysis were conducted using "Seurat", "monocle", and "iTALK" packages. PDP1 was silenced to validate its influence on the target genes.

Data from public databases revealed significant upregulation of PDP1 in BC samples compared to normal tissues. A RiskScore model based on PDP1-related differential ferroptosis-related genes (FRGs) ACSL1, BNIP3, and EMC2 was developed, which effectively predicted BC patient prognosis. High-risk BC samples exhibited poorer overall survival and were associated with immune microenvironment. The model remained significant in multivariate Cox regression analysis, indicating that it could independently predict the survival of BC patients. ACSL1, BNIP3, and EMC2 were downregulated after knockdown of PDP1.

RiskScore model constructed by PDP1-ferroptosis-related genes ACSL1, BNIP3, and EMC2 is able to help predict the prognosis of BC patients.

Triple-Negative Breast Cancer (TNBC) represents a highly aggressive subtype of breast cancer with an unfavorable prognosis, characterized by minimal immune infiltration and pronounced immune suppression, resulting in a limited response to immunotherapy. In this study, a multifunctional Arsenene-Vanadene nanodot (AsV) drug delivery system is introduced, which responds to the tumor microenvironment by releasing arsenic and vanadium. Arsenic undergoes oxidation to generate highly toxic trivalent arsenic, which induces apoptosis in tumor cells while utilizing apoptotic cell debris to transiently activate the immune system. Additionally, arsenic binds to cysteine, indirectly facilitating ferroptosis. Concurrently, vanadium's redox cycling properties are harnessed to trigger a Fenton-like reaction, promoting lipid peroxidation. Furthermore, ferroptosis is enhanced through the depletion of glutathione and inactivation of glutathione peroxidase 4 (GPX4), leading to the release of damage-associated molecular patterns and thereby amplifying the anti-tumor immune response. This study represents the first instance of integrating arsenene's apoptosis-inducing properties with vanadium's ferroptosis-enhancing effects, providing a synergistic approach to improving the immunotherapeutic response and offering a potential strategy for enhancing TNBC prognosis. STATEMENT OF SIGNIFICANCE: Triple-negative breast cancer (TNBC) exhibits resistance to immunotherapy due to its highly immunosuppressive tumor microenvironment. In this study, tumour-responsive Arsenene-Vanadene nanodots (AsV) were developed to induce a synergistic effect by triggering apoptosis and ferroptosis through microenvironment-specific mechanisms. The arsenic component generates cytotoxic trivalent arsenic, promoting apoptosis while binding to cysteine, thereby reducing GSH synthesis. Simultaneously, vanadium initiates lipid peroxidation through Fenton-like reactions and disruption of the glutathione/GPX4 axis, further amplifying ferroptotic cell death. This dual-action system transforms tumor cell debris into immune-stimulating signals while circumventing conventional immunotherapy limitations. As the first strategy integrating arsenic-induced apoptosis with vanadium-enhanced ferroptosis, this approach provides a mechanistic framework to overcome TNBC immunosuppression through coordinated cell death pathways, demonstrating potential for precision nanomedicine applications.

The process of apoptosis plays a crucial role in tissue homeostasis, immune system regulation, and organ formation. Apoptotic vesicles (ApoEVs) are involved in efferocytosis, the process by which phagocytes ingest dead cells. ApoEVs also have potential therapeutic applications in cancer treatment, ischemic diseases, and their anti-inflammatory properties make them incredibly versatile for medical applications. These vesicles can induce apoptosis in cancer cells, provide tumor antigens for cancer vaccines, and even serve as effective drug delivery systems. Moreover, they can target hypoxic cells, inhibit inflammatory cell death pathways, and promote tissue regeneration. Also, their potential in addressing inflammatory disorders such as gastrointestinal ailments, osteoarthritis, and diabetes is promising. Additionally, ApoEVs can polarize anti-inflammatory immune cells and suppress inflammatory immune responses which make them a viable option for addressing the unmet need for novel anti-inflammatory medications. Despite a wealth of reviews examining the applications of ApoEVs, very few have thoroughly investigated the mechanisms underlying their anti-inflammatory effects. This distinctive approach positions the current review as timely and immensely relevant, illuminating the intriguing ways these entities function beyond their established advantages.

Currently, cancer immunotherapy strategies are primarily formulated based on the patient's present condition, representing a "static" treatment approach. However, cancer progression is inherently "dynamic," as the immune environment is not fixed but undergoes continuous changes. This dynamism is characterized by the ongoing interactions between tumor cells and immune cells, which ultimately lead to alterations in the tumor immune microenvironment. This process can be effectively elucidated by the concept of cancer immunoediting, which divides tumor development into three phases: "elimination," "equilibrium," and "escape." Consequently, adjusting immunotherapy regimens based on these distinct phases may enhance patient survival and improve prognosis. Targeting ferroptosis is an emerging area in cancer immunotherapy, and our findings reveal that the antioxidant systems associated with ferroptosis possess dual roles, functioning differently across the three phases of cancer immunoediting. Therefore, this review delve into the dual role of the ferroptosis antioxidant system in tumor development and progression. It also propose immunotherapy strategies targeting ferroptosis at different stages, ultimately aiming to illuminate the significant implications of targeting ferroptosis at various phases for cancer immunotherapy.

The abscopal effect in radiotherapy (RT) refers to the phenomenon where localized radiation treatment causes regression of distant, nonirradiated tumors. Although rare, recent research shows that combining radiation with immunotherapies, such as immune checkpoint inhibitors, can enhance this effect. The interaction between radiation-induced cell death, immune responses, and the tumor microenvironment manifests in competing biologic mechanisms resulting in complex immunologic outcomes. In order to maximize the therapeutic advantages of the immunogenic effect of RT in the future, further studies are needed to fully understand its biologic underpinnings.

Normal cells begin to grow indefinitely and immortalize to form tumor cells after an external stimulus resulting in a genetic mutation. Effective killing of tumor cells is the basis of various cancer therapies. Ferroptosis is a class of cell death types dependent on iron and cellular lipid peroxidation. Tumors themselves are iron-dependent, and conventional radiotherapy also sensitizes cancer cells to ferroptosis. Increasing the sensitivity of tumor cells to ferroptosis may be a potential therapeutic strategy to overcome the resistance mechanisms of conventional cancer therapy. Long noncoding RNAs (LncRNAs) are a class of transcripts more than 200 nucleotides in length that regulate gene expression at multiple levels and are involved in biological processes such as cell differentiation, cell cycle arrest, and maintenance of tumor stemness. Recent studies have found that lncRNAs regulate ferroptosis of tumor cells through multiple mechanisms and may influence or ameliorate tumor resistance to chemotherapeutic agents. With the continuous maturation of nanomaterials technology, it may provide new means for cancer treatment by regulating the levels of ferroptosis-related lncRNAs inside tumors as well as increasing the levels of Fe2+ and ROS inside tumors. In this paper, we systematically introduce the regulatory mechanism of lncRNAs in ferroptosis, the role of ferroptosis in tumor immunotherapy and the application of lncRNAs combined with ferroptosis in nanomaterials, which provides new perspectives for tumor therapy.

PCBP1 is a multifunctional adaptor protein, whose function as an iron chaperone and epigenetic regulator of several chemical messengers involved in ferroptosis has garnered much attention. Herein, this review, several attempts have been made to simplify our understanding of the complex roles of PCBP1. The review begins by elucidating the relevance of PCBP1 in key events governing ferroptosis. We expeditiously shed light on some of the important mechanisms that have critical implications for the ferroptosis landscape. For instance, senescence, EMT, hypoxia, and regulation of the cell cycle and immune checkpoints, among others, have been demonstrated to influence ferroptosis sensitivity to varying degrees. Thus, this review entails a conscious attempt to carefully examine the relevance of PCBP1 in such potential mechanisms. Furthermore, we investigated the therapeutic relevance of PCBP1 in tumor biology and autoimmunity, while underscoring the contrasting perspective of ferroptosis targeting across the disease spectrum. Finally, we debate the different strategies that can be exploited to target PCBP1 in promoting or inhibiting ferroptosis.

The accelerating growth of scientific literature overwhelms our capacity to manually distil complex phenomena like molecular networks linked to diseases. Moreover, biases in biomedical research and database annotation limit our interpretation of facts and generation of hypotheses. ENQUIRE (Expanding Networks by Querying Unexpectedly Inter-Related Entities) offers a time- and resource-efficient alternative to manual literature curation and database mining. ENQUIRE reconstructs and expands co-occurrence networks of genes and biomedical ontologies from user-selected input corpora and network-inferred PubMed queries. Its modest resource usage and the integration of text mining, automatic querying, and network-based statistics mitigating literature biases makes ENQUIRE unique in its broad-scope applications. For example, ENQUIRE can generate co-occurrence gene networks that reflect high-confidence, functional networks. When tested on case studies spanning cancer, cell differentiation, and immunity, ENQUIRE identified interlinked genes and enriched pathways unique to each topic, thereby preserving their underlying context specificity. ENQUIRE supports biomedical researchers by easing literature annotation, boosting hypothesis formulation, and facilitating the identification of molecular targets for subsequent experimentation.

As a novel form of nonapoptotic cell death, ferroptosis is developing into a promising therapeutic target of dedifferentiating and therapy-refractory cancers. However, its application in pancreatic cancer is still unknown. In the preliminary research, we found that F-box and WD repeat domain-containing 7 (FBW7) inhibited the migration and proliferation of pancreatic cancer cells through its substrate c-Myc. We further found that another key substrate of FBW7, KLF5, could inhibit ferroptosis. Inhibiting KLF5 significantly enhances the cytotoxicity of oxaliplatin rather than other chemotherapy drugs. Mechanistically, we found that KLF5 inhibited the expression of heme oxygenase 1 (HMOX1) via repressing zinc finger E-box-binding homeobox 1 (ZEB1). Inhibition of KLF5 facilitated the cytotoxic effect of oxaliplatin via promoting ferroptosis. Oxaliplatin combined with KLF5 inhibitor significantly potentiated cell death in vitro and inhibited tumor growth in vivo compared with either treatment alone. These results reveal a critical role of KLF5 in sensitized chemotherapy of pancreatic cancer, and suggest that ferroptosis combined with platinum-based chemotherapy rather than gemcitabine-based chemotherapy is expected to bring better therapeutic effects.

Platinum-based anticancer chemotherapy (PAC) represents a cornerstone in cancer treatment, retaining its status as the gold standard therapy. However, PAC's efficacy is countered by significant toxicities, such as nephrotoxicity, ototoxicity, and neurotoxicity. Recent studies have linked these toxicities to ferroptosis, characterized by iron accumulation, reactive oxygen species generation, and lipid peroxidation. This review explores the mechanisms underlying PAC-induced toxicities, focusing on the involvement of ferroptosis with three major PAC drugs-cisplatin, carboplatin, and oxaliplatin. Further, we provide a comprehensive analysis of the natural product mitigation of PAC-induced ferroptotic toxicity.

The mechanistic role of ferroptosis in cisplatin- and oxaliplatin-induced toxicities has been investigated, while studies on carboplatin-induced ferroptotic toxicities are lacking. Natural compounds targeting molecular pathways of ferroptosis have been explored to mitigate PAC-induced ferroptotic toxicity.

While ferroptosis in cisplatin- and oxaliplatin-induced toxicities has been investigated, there remains a notable dearth of studies examining its involvement in carboplatin-induced toxicities. Hence, further exploration is warranted to define the role of ferroptosis in carboplatin-induced toxicities, and its further mitigation. Moreover, in-depth mechanistic evaluation is necessary to establish natural products evaluated against PAC-induced ferroptosis, as PAC adjuvants.

Ferroptosis, a regulated form of cell death distinct from apoptosis and necrosis. Key hallmarks include iron-dependent lipid peroxidation, glutathione depletion, and intracellular iron accumulation, all of which are counteracted by specific cellular defenses. However, the immunosuppressive effects of ferroptosis induction in cancer immunotherapy remain unresolved. This review summarizes the recent advancements in ferroptosis research, focusing on its defensive mechanisms. It analyzes how ferroptosis affects both cancer and immune cells, highlighting its potential inhibitory effects on anti-tumor immunity and possible promotion of pro-tumor immune responses. Finally, this review briefly introduces case studies that combined ferroptosis induction with immunotherapy, offering novel perspectives for cancer treatment.

Ferroptosis has been shown to play a crucial role in preventing cancer development, but the underlying mechanisms of dysregulated genes and genetic alternations driving cancer development by regulating ferroptosis remain unclear. Here, we showed that the synergistic role of ELF3 overexpression and PTEN deficiency in driving lung cancer development was highly dependent on the regulation of ferroptosis. Human ELF3 (hELF3) overexpression in murine lung epithelial cells only caused hyperplasia with increased proliferation and ferroptosis. hELF3 overexpression and Pten genetic disruption significantly induced lung tumor development with increased proliferation and inhibited ferroptosis. Mechanistically, we found it was due to the induction of SCL7A11, a typical ferroptosis inhibitor, and ELF3 directly and positively regulated SCL7A11 in the PTEN-deficient background. Erastin-mediated inhibition of SCL7A11 induced ferroptosis in cells with ELF3 overexpression and PTEN deficiency and thus inhibited cell colony formation and tumor development. Clinically, human lung tumors showed a negative correlation between ELF3 and PTEN expression and a positive correlation between ELF3 and SCL7A11 in a subset of human lung tumors with PTEN-low expression. ELF3 and SCL7A11 expression levels were negatively associated with lung cancer patients' survival rates. In summary, ferroptosis induction can effectively attenuate lung tumor development induced by ELF3 overexpression and PTEN downregulation or loss-of-function mutations.

Since the emergence of the hot topic of "ferroptosis," numerous studies have explored its role in hepatocellular carcinoma (HCC), revealing its significance in the disease's pathogenesis, progression, and treatment. However, there remains a significant gap in the quantitative analysis of ferroptosis in HCC. Therefore, this study aims to comprehensively assess the research progress and evolution in this field through bibliometric and citation analysis.

On June 27, 2024, the author conducted a literature search, extracting relevant publications from the Web of Science Core Collection (WOSCC) Science Citation Index Expanded (SCIE) spanning from January 2010 to December 2023. Subsequently, the compiled documents were subjected to bibliometric evaluation and analysis using visualization tools such as R package "bibliometrix", CiteSpace and VOSviewer.

The search yielded 576 papers by 3,925 authors, encompassing contributions from 34 countries and 685 institutions, published across 250 journals, including 25,889 co-cited references from 2,600 journals. Notably, China leads with a significant publication count of 481 articles (accounting for 83.5%) and demonstrates the strongest collaboration with the United States. The multifaceted role of ferroptosis in hepatocellular carcinoma (HCC) has garnered considerable attention. In recent years, research into disease prognosis, the tumor microenvironment, and targeted therapies involving immunology has become key themes and emerging frontiers in this field.

This study meticulously compiled and analyzed the current discourse and emerging perspectives on ferroptosis in HCC. Identifying research trends and hotspots offers valuable guidance for future investigations and provides a basis for the development of novel therapeutic strategies to improve HCC prognosis and treatment outcomes.

Radiotherapy plays a crucial role in the treatment of advanced breast cancer, but the increased antioxidant system, especially the rise in glutathione (GSH), presents a significant obstacle to its effectiveness. To address this challenge, a versatile GSH-depleted photodynamic nanoadjuvant is developed to augment the efficacy of radiotherapy for breast cancer treatment. This nanoadjuvant operates within the tumor microenvironment to effectively deplete intracellular GSH through a sequence of cascaded processes, including GSH exhaustion, biosynthetic inhibition, and photodynamic oxidation. This leads to a notable accumulation of lipid peroxides (LPO) and subsequent suppression of glutathione peroxidase 4 (GPX4) activity. Consequently, the combined GSH depletion induced by the nanoadjuvant markedly promotes nonferrous ferroptosis, thereby contributing to the augmentation of antitumor efficiency during radiotherapy in breast cancer. This work presents an innovative approach to designing and synthesizing biocompatible nanoadjuvants with the goal of improving the efficacy of radiotherapy for breast cancer in prospective clinical scenarios.

Immunotherapies for cancer, specifically immune checkpoint inhibition (ICI), have shown potential in reactivating the body's immune response against tumors. However, there are challenges to overcome in addressing drug resistance and improving the effectiveness of these treatments. Recent research has highlighted the relationship between ferroptosis and the immune system within immune cells and the tumor microenvironment (TME), suggesting that combining targeted ferroptosis with immunotherapy could enhance anti-tumor effects. This review explores the potential of using immunotherapy to target ferroptosis either alone or in conjunction with other therapies like immune checkpoint blockade (ICB) therapy, radiotherapy, and nanomedicine synergistic treatments. It also delves into the roles of different immune cell types in promoting anti-tumor immune responses through ferroptosis. Together, these findings provide a comprehensive understanding of synergistic immunotherapy focused on ferroptosis and offer innovative strategies for cancer treatment.

In the face of cell damage, cells can initiate a response ranging from survival to death, the balance being crucial for tissue homeostasis and overall health. Cell death, in both accidental and regulated forms, plays a fundamental role in maintaining tissue homeostasis. Among the regulated mechanisms of cell death, ferroptosis has garnered attention for its iron-dependent phospholipid (PL) peroxidation and its implications in aging and age-related disorders, as well as for its therapeutic relevance. In this review, we provide an overview of the mechanisms, regulation, and physiological and pathological roles of ferroptosis. We present new insights into the relationship between ferroptosis, cellular senescence and aging, emphasizing how alterations in ferroptosis pathways contribute to aging-related tissue dysfunction. In addition, we examine the therapeutic potential of ferroptosis in aging-related diseases, offering innovative insights into future interventions aimed at mitigating the effects of aging and promoting longevity.

Metabolic plasticity and ferroptosis are essential for colorectal cancer (CRC) progression. The effects and prognostic value of metabolic plasticity- and ferroptosis-related genes (MPFRGs) in CRC remain unclear. We established a prognostic model for CRC patients by identifying important genes in metabolic plasticity and ferroptosis. Data of CRC patients were retrieved from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus; MPFRG data were obtained from GeneCards and FerrDb. We performed functional (to explore differences between the two metabolic subtypes) and single-sample gene set (to assess the immune environment) enrichment analyses. Immunophenotype, tumor immunological dysfunction, and exclusion scores were assessed to determine patient immune responses. A least absolute shrinkage and selection operator-Cox regression model comprising 10 significant differentially expressed genes of metabolic plasticity and ferroptosis (MPFDEGs) was constructed using TCGA training cohort and validated using the GSE17536 and GSE39582 datasets. We established a nomogram comprising metabolic plasticity- and ferroptosis-based signatures, revealing the clinical application and potential molecular mechanisms underlying the role of MPFRGs in CRC. Our model (developed based on 10 MPFDEGs) is efficient for calculating the overall survival of CRC patients. Our findings provide new strategies for the clinical management and individualized treatment of these patients.

Significance: Numerous disorders are linked to ferroptosis, a form of programmed cell death triggered by lipid peroxidation accumulation rather than apoptosis. Inflammation is the body's defensive response to stimuli and is also caused by inflammatory chemicals that can harm the body. The treatment of inflammatory diseases by focusing on the signaling pathways and mechanisms of ferroptosis has emerged as a new area worthy of extensive research. Recent Advances: Studies in cellular and animal models of inflammatory diseases have shown that ferroptosis markers are activated and lipid peroxidation levels are increased. Natural products (NPs) are gaining importance due to their ability to target ferroptosis pathways, particularly the Nuclear factor E2-related factor 2 signaling pathway, thereby suppressing inflammation and the release of pro-inflammatory cytokines. Critical Issues: This article provides an overview of ferroptosis, focusing on the signaling pathways and mechanisms connecting it to inflammation. It also explores the potential use of NPs as a treatment for inflammatory diseases and ferroptosis. Future Directions: NPs offer unique advantages, including multicomponent properties, multi-bio-targeting capabilities, and minimal side effects. Further research may facilitate the early clinical application of NPs to develop innovative treatment strategies. Antioxid. Redox Signal. 41, 976-991.

Inositol 1,4,5-trisphosphate receptors (IP3Rs) play a crucial role in maintaining intracellular/cytosolic calcium ion (Ca2+i) homeostasis. The release of Ca2+ from IP3Rs serves as a second messenger and a modulatory factor influencing various intracellular and interorganelle communications during both physiological and pathological processes. Accumulating evidence from in vitro, in vivo, and clinical studies supports the notion that the overactivation of IP3Rs is linked to the pathogenesis of various cardiac conditions. The overactivation of IP3Rs results in the dysregulation of Ca2+ concentration ([Ca2+]) within cytosolic, mitochondrial, and nucleoplasmic cellular compartments. In cardiovascular pathologies, two isoforms of IP3Rs, i.e., IP3R1 and IP3R2, have been identified. Notably, IP3R1 plays a pivotal role in cardiac ischemia and diabetes-induced arrhythmias, while IP3R2 is implicated in sepsis-induced cardiomyopathy and cardiac hypertrophy. Furthermore, IP3Rs have been reported to be involved in various programmed cell death (PCD) pathways, such as apoptosis, pyroptosis, and ferroptosis underscoring their multifaceted roles in cardiac pathophysiology. Based on these findings, it is evident that exploring potential therapeutic avenues becomes crucial. Both genetic ablation and pharmacological intervention using IP3R antagonists have emerged as promising strategies against IP3R-related pathologies suggesting their potential therapeutic potency. This review summarizes the roles of IP3Rs in cardiac physiology and pathology and establishes a foundational understanding with a particular focus on their involvement in the various PCD pathways within the context of cardiovascular diseases.

Ferroptosis is a newly discovered form of cell death that is influenced by iron levels and is triggered by cellular metabolism and excessive lipid peroxidation. Epigenetic regulation plays a crucial role in the development and progression of diseases, making it essential to understand these mechanisms in order to identify potential targets for drug development and clinical treatment. The intersection of ferroptosis and epigenetics has opened up new avenues for research in drug development, offering innovative strategies for combating diseases. Recent studies have shown that epigenetic modifications can impact pathways related to ferroptosis, potentially leading to organ dysfunction. Despite the increasing focus on this relationship, the role of epigenetic regulation in drug development remains largely unexplored. This article explores current research on the interplay between epigenetic regulation and ferroptosis, delving into their regulatory mechanisms and discussing the effects of existing epigenetic modification regulators on diseases. Additionally, we highlight ongoing research on epigenetic factors involved in targeting ferroptosis in cancer, providing new insights for the development of cancer treatments.

Ferroptosis, an iron-dependent form of non-apoptotic regulated cell death, is induced by the accumulation of lipid peroxides on cellular membranes. Over the past decade, ferroptosis has emerged as a crucial process implicated in various physiological and pathological systems. Positioned as an alternative modality of cell death, ferroptosis holds promise for eliminating cancer cells that have developed resistance to apoptosis induced by conventional therapeutics. This has led to a growing interest in leveraging ferroptosis for cancer therapy across diverse malignancies. Gliomas are tumors arising from glial or precursor cells, with glioblastoma (GBM) being the most common malignant primary brain tumor that is associated with a dismal prognosis. This review provides a summary of recent advancements in the exploration of ferroptosis-sensitizing methods, with a specific focus on their potential application in enhancing the treatment of gliomas. In addition to summarizing the therapeutic potential, this review also discusses the intricate interplay of ferroptosis and its potential tumor-promoting roles within gliomas. Recognizing these dual roles is essential, as they could potentially complicate the therapeutic benefits of ferroptosis. Exploring strategies aimed at circumventing these tumor-promoting roles could enhance the overall therapeutic efficacy of ferroptosis in the context of glioma treatment.

Non-thermal plasma (NTP) has shown promising anti-cancer effects, but there is still limited knowledge about the underlying cell death mechanisms induced by NTP and inherent differences between NTP treatment modalities. This study aimed to investigate four major regulated cell death (RCD) pathways, namely apoptosis, pyroptosis, necroptosis, and ferroptosis, in melanoma cancer cells following NTP treatment, and to provide an overview of molecular mechanistic differences between direct and indirect NTP treatment modalities. To discriminate which cell death pathways were triggered after treatment, specific inhibitors of apoptosis, pyroptosis, necroptosis, and ferroptosis were evaluated. RCD-specific molecular pathways were further investigated to validate the findings with inhibitors. Both direct and indirect NTP treatment increased caspase 3/7 and annexin V expression, indicative of apoptosis, as well as lipid peroxidation, characteristic of ferroptosis. Pyroptosis, on the other hand, was only induced by direct NTP treatment, evidenced by increased caspase 1 activity, whereas necroptosis was stimulated in a cell line-dependent manner. These findings highlight the molecular differences and implications of direct and indirect NTP treatment for cancer therapy. Altogether, activation of multiple cell death pathways offers advantages in minimizing treatment resistance and enhancing therapeutic efficacy, particularly in a combination setting. Understanding the mechanisms underlying NTP-induced RCD will enable the development of strategic combination therapies targeting multiple pathways to achieve cancer lethality.

Ferroptosis, defined by the suppression of glutathione peroxidase-4 (GPX4) and iron overload, is a distinctive form of regulated cell death. Our in-depth research identifies matrix metalloproteinase-9 (MMP9) as a critical modulator of ferroptosis through its influence on GPX4 and iron homeostasis. Employing an innovative MMP9 construct without collagenase activity, we reveal that active MMP9 interacts with GPX4 and glutathione reductase, reducing GPX4 expression and activity. Furthermore, MMP9 suppresses key transcription factors (SP1, CREB1, NRF2, FOXO3, and ATF4), alongside GPX1 and ferroptosis suppressor protein-1 (FSP1), thereby disrupting the cellular redox balance. MMP9 regulates iron metabolism by modulating iron import, storage, and export via a network of protein interactions. LC-MS/MS has identified 83 proteins that interact with MMP9 at subcellular levels, implicating them in ferroptosis regulation. Integrated pathway analysis (IPA) highlights MMP9's extensive influence on ferroptosis pathways, underscoring its potential as a therapeutic target in conditions with altered redox homeostasis and iron metabolism.

The progression of tumours is related to abnormal phospholipid metabolism. This study is anticipated to present a fresh perspective for disease therapy targets of hepatocarcinoma caused by hepatitis B virus in the future by screening feature genes related to phospholipid metabolism.

This study analysed GSE121248 to pinpoint differentially expressed genes (DEGs). By examining the overlap between the metabolism-related genes and DEGs, the research focused on the genes involved in phospholipid metabolism. To find feature genes, functional enrichment studies were carried out and a network diagram was proposed. These findings were validated via data base of The Cancer Genome Atlas (TCGA). Further analyses included immune infiltration studies and metabolomics. Finally, the relationships between differentially abundant metabolites and feature genes were confirmed by molecular docking, providing a thorough comprehension of the molecular mechanisms.

The seven genes with the highest degree of connection (PTGS2, IGF1, SPP1, BCHE, NR1I2, NAMPT, and FABP1) were identified as feature genes. In the TCGA database, the seven feature genes also had certain diagnostic efficiency. Immune infiltration analysis revealed that feature genes regulate the infiltration of various immune cells. Metabolomics successfully identified the different metabolites of the phospholipid metabolism pathway between patients and normal individuals. The docking study indicated that different metabolites may play essential roles in causing disease by targeting feature genes.

In this study, for the first time, it reveals the possible involvement of genes linked to phospholipid metabolism-related genes using bioinformatics analysis. Identifying genes and probable therapeutic targets could provide clues for the further treatment of disease.

This study aimed to investigate the role of JMJD2A in radiotherapy tolerance of esophageal squamous cell carcinoma (ESCC).

The levels of H3K9me3 modification were analyzed in anti-PD-1 therapy non-responder or responder patients, and the expression differences of H3K9me3-related modifying enzymes were assessed in TCGA-ESCC and ICGC cohorts. Subsequently, JMJD2A was knocked down in ESCC cells using CRISPR-Cas9 or lentivirus-mediated shRNA, and changes in malignant behavior of ESCC cells were observed. RNA-seq, ATAC-seq, and ChIP-seq analyses were then conducted to investigate the genes and downstream signaling pathways regulated by JMJD2A, and functional validation experiments were performed to analyze the role of downstream regulated genes and pathways in ESCC malignant behavior and immune evasion.

JMJD2A was significantly overexpressed in ESCC and anti-PD-1 therapy non-responders. Knockdown or deletion of JMJD2A significantly promoted the malignant behavior and immune evasion of ESCC. JMJD2A facilitated the structural changes in chromatin and promoted the binding of SMARCA4 to super-enhancers, thereby inducing the expression of GPX4. This resulted in the inhibition of radiation-induced DNA damage and cell ferroptosis, ultimately promoting the malignant behavior and immune evasion of ESCC cells.

JMJD2A plays an indispensable role in the malignant behavior and immune evasion of ESCC. It regulates the binding of SMARCA4 to super-enhancers and affects the chromatin's epigenetic landscape, thereby promoting the expression of GPX4 and attenuating iron-mediated cell death caused by radiotherapy. Consequently, it triggers the malignant behavior and immune evasion of ESCC cells.

Mesothelioma, an uncommon yet highly aggressive malignant neoplasm, presents challenges in the effectiveness of current therapeutic approaches. Ferroptosis, a non-apoptotic mechanism of cellular demise, exhibits a substantial association with the progression of diverse cancer forms. It is important to acknowledge that there exists a significant association between ferroptosis and the advancement of various forms of cancer. Nevertheless, the precise role of ferroptosis regulatory factors within the context of mesothelioma remains enigmatic. In our investigation, we initially scrutinized the prognostic significance of 24 ferroptosis regulatory factors in the realm of mesothelioma. Our observations unveiled that heightened expression levels of CARS1, CDKN1A, TFRC, FANCD2, FDFT1, HSPB1, SLC1A5, SLC7A11, coupled with reduced DPP4 expression, were indicative of an unfavorable prognosis. Built upon the nine previously discussed prognostic genes, the ferroptosis prognostic model offers a reliable means to forecast mesothelioma patients' survival with a substantial degree of precision. Furthermore, a notable correlation emerged between these prognostic ferroptosis regulators and parameters such as immune cell infiltration, tumor mutation burden, microsatellite instability, and PD-L1 expression in the context of mesothelioma. Within this cadre of nine ferroptosis regulatory factors with prognostic relevance, FANCD2 exhibited the most pronounced prognostic influence, as elucidated by our analyses. Subsequently, we executed a validation process employing clinical specimens sourced from our institution, thus confirming that heightened FANCD2 expression is a discernible harbinger of an adverse prognosis in the context of mesothelioma. In vitro experiments revealed that knocking down FANCD2 markedly suppressed the proliferation, migration, and ability of mesothelioma cells to attract immune cells. Furthermore, our findings also showed that reducing FANCD2 levels heightened the vulnerability of mesothelioma cells to inducers of ferroptosis. Furthermore, an extensive pan-cancer analysis uncovered a robust association between FANCD2 and the gene expression linked to immune checkpoints, thereby signifying an adverse prognosis across a broad spectrum of cancer types. Additional research is warranted to validate these findings.

Ferroptosis, a unique form of regulated cell death driven by iron-dependent lethal lipid peroxidation, is implicated in various stress-related diseases like neurodegeneration, vasculopathy, and metabolic disturbance. Stress-related diseases encompass widespread medical disorders that are influenced or exacerbated by stress. These stressors can manifest in various organ or tissue systems and have significant implications for human overall health. Understanding ferroptosis in these diseases offers insights for therapeutic strategies targeting relevant pathways. This review explores ferroptosis mechanisms, its role in pathophysiology, its connection to stress-related diseases, and the potential of ferroptosis-targeted nanomedicines in treating conditions. This monograph also delves into the engineering of ferroptosis-targeted nanomedicines for tackling stress-related diseases, including cancer, cardia-cerebrovascular, neurodegenerative, metabolic and inflammatory diseases. Anyhow, nanotherapy targeting ferroptosis holds promise by both promoting and suppressing ferroptosis for managing stress-related diseases.

Amino acid metabolism plays a pivotal role in tumor microenvironment, influencing various aspects of cancer progression. The metabolic reprogramming of amino acids in tumor cells is intricately linked to protein synthesis, nucleotide synthesis, modulation of signaling pathways, regulation of tumor cell metabolism, maintenance of oxidative stress homeostasis, and epigenetic modifications. Furthermore, the dysregulation of amino acid metabolism also impacts tumor microenvironment and tumor immunity. Amino acids can act as signaling molecules that modulate immune cell function and immune tolerance within the tumor microenvironment, reshaping the anti-tumor immune response and promoting immune evasion by cancer cells. Moreover, amino acid metabolism can influence the behavior of stromal cells, such as cancer-associated fibroblasts, regulate ECM remodeling and promote angiogenesis, thereby facilitating tumor growth and metastasis. Understanding the intricate interplay between amino acid metabolism and the tumor microenvironment is of crucial significance. Expanding our knowledge of the multifaceted roles of amino acid metabolism in tumor microenvironment holds significant promise for the development of more effective cancer therapies aimed at disrupting the metabolic dependencies of cancer cells and modulating the tumor microenvironment to enhance anti-tumor immune responses and inhibit tumor progression.

Copper is an important metal micronutrient, required for the balanced growth and normal physiological functions of human organism. Copper-related toxicity and dysbalanced metabolism were associated with the disruption of intracellular respiration and the development of various diseases, including cancer. Notably, copper-induced cell death was defined as cuproptosis which was also observed in malignant cells, representing an attractive anti-cancer instrument. Excess of intracellular copper leads to the aggregation of lipoylation proteins and toxic stress, ultimately resulting in the activation of cell death. Differential expression of cuproptosis-related genes was detected in normal and malignant tissues. Cuproptosis-related genes were also linked to the regulation of oxidative stress, immune cell responses, and composition of tumor microenvironment. Activation of cuproptosis was associated with increased expression of redox-metabolism-regulating genes, such as ferredoxin 1 (FDX1), lipoic acid synthetase (LIAS), lipoyltransferase 1 (LIPT1), dihydrolipoamide dehydrogenase (DLD), drolipoamide S-acetyltransferase (DLAT), pyruvate dehydrogenase E1 subunit alpha 1 (PDHA1), and pyruvate dehydrogenase E1 subunit beta (PDHB)). Accordingly, copper-activated network was suggested as an attractive target in cancer therapy. Mechanisms of cuproptosis and regulation of cuproptosis-related genes in different cancers and tumor microenvironment are discussed in this study. The analysis of current findings indicates that therapeutic regulation of copper signaling, and activation of cuproptosis-related targets may provide an effective tool for the improvement of immunotherapy regimens.

This review investigates the role of ferroptosis in combating chemotherapy resistance in ovarian cancer, with a focus on its underlying mechanisms and therapeutic implications.

A database search was conducted up to December 2023 using PubMed, Scopus, Google Scholar, Web of Science, and the Cochrane Library. The keywords "ovarian cancer," "ferroptosis," "cisplatin," and "cisplatin resistance" were employed. We included studies that offered original data on the application of ferroptosis in platinum-based chemotherapy, focusing on both in-vitro and in-vivo research models.

Our review reveals that ferroptosis significantly influences drug resistance in ovarian cancer. It investigates the existing studies to understand the role of ferroptosis in platinum resistance and explores its underlying mechanisms and assesses potential therapeutic strategies that uses ferroptosis to improve outcomes. The findings underscore the importance of ferroptosis in enhancing the effectiveness of platinum-based treatments and improving patient prognosis.

The potential of ferroptosis induction to develop novel therapeutic strategies against ovarian cancer, especially in cisplatin-resistant cases, is promising. The preliminary nature of these findings highlights the necessity for further research to bring these insights into clinical practice. This would not only improve treatment outcomes and prognosis but also encourage ongoing studies into ferroptosis as a viable therapeutic approach.

Branched gold and silver nanoparticles coated with polydopamine (Au-Ag-PDA) demonstrate high photothermal conversion efficiency. Utilizing umbilical cord mesenchymal stem cell membranes (MSCM) as an effective drug delivery system, our preliminary studies investigated the suppression of sebum secretion in sebaceous glands using MSCM-coated Au-Ag-PDA nano-particles (Au-Ag-PDA@MSCM) combined with 808 nm laser irradiation, showing potential for dermatological applications in acne treatment.

This study employs proteomic analysis, complemented by subsequent techniques such as Western blotting (WB), small interfering RNA (siRNA), and transmission electron microscopy, to further investigate the differential mechanisms by which Au-Ag-PDA and Au-Ag-PDA@MSCM-mediated photothermal therapy (PTT) suppress sebum secretion.

Our proteomic analysis indicated mitochondrial respiratory chain damage in sebaceous gland tissues post-PTT, with further validation revealing ferroptosis in sebaceous cells and tissues. Acyl-CoA Synthetase Long-Chain Family Member 4 (Acsl4) has been identified as a critical target, with Au-Ag-PDA@MSCM demonstrating enhanced ferroptotic effects.

These findings significantly advance our understanding of how PTT mediated by Au-Ag-PDA@MSCM nanoparticles reduces sebum secretion and underscore the pivotal role of MSCM in inducing ferroptosis in sebaceous glands, thus providing a robust theoretical foundation for employing PTT via specific molecular pathways in acne treatment.

Ferroptosis is an unconventional programmed cell death mode caused by phospholipid peroxidation dependent on iron. Emerging immunotherapies (especially immune checkpoint inhibitors) have the potential to enhance lung cancer patients' long-term survival. Although immunotherapy has yielded significant positive applications in some patients, there are still many mechanisms that can cause lung cancer cells to evade immunity, thus leading to the failure of targeted therapies. Immune-tolerant cancer cells are insensitive to conventional death pathways such as apoptosis and necrosis, whereas mesenchymal and metastasis-prone cancer cells are particularly vulnerable to ferroptosis, which plays a vital role in mediating immune tolerance resistance by tumors and immune cells. As a result, triggering lung cancer cell ferroptosis holds significant therapeutic potential for drug-resistant malignancies. Here, we summarize the mechanisms underlying the suppression of ferroptosis in lung cancer, highlight its function in the lung cancer immune microenvironment, and propose possible therapeutic strategies.

As a newly identified regulated cell death, ferroptosis is a metabolically driven process that relies on iron and is associated with polyunsaturated fatty acyl peroxidation, elevated levels of reactive oxygen species (ROS), and mitochondrial damage. This distinct regulated cell death is dysregulated in various cancers; activating ferroptosis in malignant cells increases cancer immunotherapy and chemoradiotherapy responses across different malignancies. Over the last decade, accumulating research has provided evidence of cross-talk between non-coding RNAs (ncRNAs) and competing endogenous RNA (ceRNA) networks and highlighted their significance in developing and progressing malignancies. Aside from pharmaceutical agents to regulate ferroptosis, recent studies have shed light on the potential of restoring dysregulated ferroptosis-related ceRNA networks in cancer treatment. The present study provides a comprehensive and up-to-date review of the ferroptosis significance, ferroptosis pathways, the role of ferroptosis in cancer immunotherapy and chemoradiotherapy, ceRNA biogenesis, and ferroptosis-regulating ceRNA networks in different cancers. The provided insights can offer the authorship with state-of-the-art findings and future perspectives regarding the ferroptosis and ferroptosis-related ceRNA networks and their implication in the treatment and determining the prognosis of affected patients.