RESUMEN

Oral squamous cell carcinoma (OSCC) is an aggressive disease whose incomplete biological comprehension contributes to the inappropriate clinical management and poor prognosis. Thus, the identification of new promising molecular targets to treat OSCC is of paramount importance. Ferroptosis is a regulated cell death caused by the iron-dependent accumulation of reactive oxygen species and the consequent oxidative damage of lipid membranes. Over the last five years, a growing number of studies has reported that OSCC is sensitive to ferroptosis induction and that ferroptosis inducers exert a remarkable antitumor effect in OSCC, even in those displaying low response to common approaches, such as chemotherapy and radiotherapy. In addition, as ferroptosis is considered an immunogenic cell death, it may modulate the immune response against OSCC. In this review, we summarize the so far identified ferroptosis regulatory mechanisms and prognostic models based on ferroptosis-related genes in OSCC. In addition, we discuss the perspective of inducing ferroptosis as a novel strategy to directly treat OSCC or, alternatively, to improve sensitivity to other approaches. Finally, we integrate data emerging from the research studies, reviewed here, through in silico analysis and we provide a novel personal perspective on the potential interconnection between ferroptosis and autophagy in OSCC.

RESUMEN

Ferroptosis, a unique form of programmed cell death, is initiated by an excess of iron accumulation and lipid peroxidation-induced damage. There is a growing body of evidence indicating that ferroptosis plays a critical role in the advancement of tumors. The increased metabolic activity and higher iron levels in tumor cells make them particularly vulnerable to ferroptosis. As a result, the targeted induction of ferroptosis is becoming an increasingly promising approach for cancer treatment. This review offers an overview of the regulatory mechanisms of ferroptosis, delves into the mechanism of action of traditional small molecule ferroptosis inducers and their effects on various tumors. In addition, the latest progress in inducing ferroptosis using new means such as proteolysis-targeting chimeras (PROTACs), photodynamic therapy (PDT), sonodynamic therapy (SDT) and nanomaterials is summarized. Finally, this review discusses the challenges and opportunities in the development of ferroptosis-inducing agents, focusing on discovering new targets, improving selectivity, and reducing toxic and side effects.

Asunto(s)

RESUMEN

The therapeutic targeting of ferroptosis requires full understanding of the molecular mechanism of this regulated cell death pathway. While lipid-derived electrophiles (LDEs), including 4-hydroxy-2-nonenal (4-HNE), are important biomarkers of ferroptosis, a functional role for these highly reactive species in ferroptotic cell death execution has not been established. Here, through mechanistic characterization of LDE-detoxification impairment, we demonstrate that LDEs mediate altered protein function during ferroptosis. Applying live cell fluorescence imaging, we first identified that export of glutathione-LDE-adducts through multidrug resistance-associated protein (MRP) channels is inhibited following exposure to a panel of ferroptosis inducers (FINs) with different modes of action (type I-IV FINs erastin, RSL3, FIN56, and FINO2). This channel inhibition was recreated by both initiation of lipid peroxidation and treatment with 4-HNE. Importantly, treatment with radical-trapping antioxidants prevented impaired LDE-adduct export when working with both FINs and lipid peroxidation initiators but not 4-HNE, pinpointing LDEs as the cause of this inhibited MRP activity observed during ferroptosis. Our findings, when combined with reports of widespread LDE alkylation of key proteins following ferroptosis induction, including MRP1, set a precedent for LDEs as critical mediators of ferroptotic cell damage. Lipid hydroperoxide breakdown to form truncated phospholipids and LDEs may fully explain membrane permeabilization and modified protein function downstream of lipid peroxidation, offering a unified explanation of the molecular cell death mechanism of ferroptosis.

Asunto(s)

RESUMEN

Ferroptosis is an iron-mediated regulatory cell death pattern characterized by oxidative damage. The molecular regulating mechanisms are related to iron metabolism, lipid peroxidation, and glutathione metabolism. Additionally, some immunological signaling pathways, such as the cyclic GMP-AMP synthase-stimulator ofinterferon genes axis, Janus kinase-signal transducer and activator of transcription 1 axis, and transforming growth factor beta 1-Smad3 axis may also participate in the regulation of ferroptosis. Studies have shown that ferroptosis is closely related to many diseases such as cancer, neurodegenerative diseases, inflammatory diseases, and autoimmune diseases. Considering the pivotal role of ferroptosis-regulating signaling in the pathogenesis of diverse diseases, the development of ferroptosis inducers or inhibitors may have significant clinical potential for the treatment of the aforementioned conditions.

RESUMEN

The latest findings in iron metabolism and the newly uncovered process of ferroptosis have paved the way for new potential strategies in anti-leukemia treatments. In the current project, we reviewed and summarized the current role of nanomedicine in the treatment and diagnosis of leukemia through a comparison made between traditional approaches applied in the treatment and diagnosis of leukemia via the existing investigations about the ferroptosis molecular mechanisms involved in various anti-tumor treatments. The application of nanotechnology and other novel technologies may provide a new direction in ferroptosis-driven leukemia therapies. The article explores the potential of targeting ferroptosis, a new form of regulated cell death, as a new therapeutic strategy for leukemia. It discusses the mechanisms of ferroptosis and its role in leukemia and how nanotechnology can enhance the delivery and efficacy of ferroptosis-inducing agents. The article not only highlights the promise of ferroptosis-targeted therapies and nanotechnology in revolutionizing leukemia treatment, but also calls for further research to overcome challenges and fully realize the clinical potential of this innovative approach. Finally, it discusses the challenges and opportunities in clinical applications of ferroptosis.

Asunto(s)

RESUMEN

Ferroptosis, a novel form of iron-dependent cell death, has emerged as a potential avenue for promoting tumor cell death by causing cell membrane rupture and the accumulation of lipid peroxides (LPO) in the cell. Since its discovery in 2012, extensive research has been conducted to explore the mechanism of ferroptosis inducers, including erastin, sulfasalazine, and sorafenib. These compounds inhibit system XC-, while Ras-selective lethal small molecule 3 (RSL3) and FION2 specifically target GPX4 to promote ferroptosis. Therefore, targeting ferroptosis presents a promising therapeutic approach for malignant tumors. While the study of ferroptosis in solid tumors has made significant progress, there is limited information available on its role in hematological tumors. This review aims to summarize the molecular mechanisms of ferroptosis inducers and discuss their clinical applications in hematological malignancies. Furthermore, the identification of non-coding RNAs (ncRNAs) and genes that regulate key molecules in the ferroptosis pathway could provide new targets and establish a molecular theoretical foundation for exploring novel ferroptosis inducers in hematological malignancies.

Asunto(s)

RESUMEN

Significance: The multifactorial nature of the mechanisms implicated in cancer development still represents a major issue for the success of established antitumor therapies. The discovery of ferroptosis, a novel form of programmed cell death distinct from apoptosis, along with the identification of the molecular pathways activated during its execution, has led to the uncovering of novel molecules characterized by ferroptosis-inducing properties. Recent advances: As of today, the ferroptosis-inducing properties of compounds derived from natural sources have been investigated and interesting findings have been reported both in vitro and in vivo. Critical Issues: Despite the efforts made so far, only a limited number of synthetic compounds have been identified as ferroptosis inducers, and their utilization is still limited to basic research. In this review, we analyzed the most important biochemical pathways involved in ferroptosis execution, with particular attention to the newest literature findings on canonical and non-canonical hallmarks, together with mechanisms of action of natural compounds identified as novel ferroptosis inducers. Compounds have been classified based on their chemical structure, and modulation of ferroptosis-related biochemical pathways has been reported. Future Directions: The outcomes herein collected represent a fascinating starting point from which to take hints for future drug discovery studies aimed at identifying ferroptosis-inducing natural compounds for anticancer therapies. Antioxid. Redox Signal. 40, 40-85.

Asunto(s)

RESUMEN

The effective and targeted treatment of resistant cancer cells presents a significant challenge. Targeting cell ferroptosis has shown remarkable efficacy against apoptosis-resistant tumors due to their elevated iron metabolism and oxidative stress levels. However, various obstacles have limited its effectiveness. To overcome these challenges and enhance ferroptosis in cancer cells, we have developed a self-powered photodynamic therapeutic tablet that integrates a ferroptosis inducer (FIN), imidazole ketone erastin (IKE). FINs augment the sensitivity of photodynamic therapy (PDT) by increasing oxidative stress and lipid peroxidation. Furthermore, they utilize the Fenton reaction to supplement oxygen, generating a greater amount of reactive oxygen species (ROS) during PDT. Additionally, PDT facilitates the release of iron ions from the labile iron pool (LIP), accelerating lipid peroxidation and inducing ferroptosis. In vitro and in vivo experiments have demonstrated a more than 85% tumor inhibition rate. This synergistic treatment approach not only addresses the limitations of inadequate penetration and tumor hypoxia associated with PDT but also reduces the required medication dosage. Its high efficiency and specificity towards targeted cells minimize adverse effects, presenting a novel approach to combat clinical resistance in cancer treatment.

Asunto(s)

RESUMEN

INTRODUCTION: The median survival of patients diagnosed with glioblastoma is very poor, despite efforts to improve the therapeutic effects of surgery, followed by treatment with temozolomide (TMZ) and ionizing radiation (IR). The utilization of TMZ or IR survivor cell models has enhanced the understanding of glioblastoma biology and the development of novel therapeutic strategies. In this present study, naïve U373 and clinically relevant U373 IRsurvivor (Surv) cells were used, as the IR-Surv cell model mimics the chronic long-term exposure to standardized radiotherapy for patients with glioblastoma in the clinic. As the role of ferroptosis in the IR survivor cell model has not previously been reported, we aimed to clarify its involvement in the clinically relevant IR-Surv glioblastoma model. METHODS: Transcriptomic alterations of ferroptosis-related genes were studied on naïve U373 and IR-Surv cell populations. To determine the effects of glutathione peroxidase inhibitors, ferroptosis-inducing agent 56 (FIN56) and Ras synthetic lethal 3 (RSL3), on the cells, several properties were assessed, including colony formation, cell viability and lipid peroxidation. RESULTS: Results from the transcriptomic analysis identified ferroptosis as a critical mechanism after radiation exposure in glioblastoma. Our findings also identified the role of ferroptosis inducers (FINs) in IR-survivor cells and suggested using FINs to treat glioblastoma. CONCLUSION: FINs serve an important role in radioresistant cells; thus, the results of the present study may contribute to improving survival in patients with glioblastoma.

Asunto(s)

RESUMEN

Ferroptosis is a new iron-dependent cell death mode, which is different from the other types of programmed cell death, such as apoptosis, necrosis, and autophagy. Ferroptosis is characterized by a process in which fatal lipids from lipid peroxidation accumulate in cells and eventually lead to cell death. Alcohol-related liver disease (ALD) is a type of liver injury caused by excessive alcohol intake. Alcohol-related liver disease is a broad-spectrum disease category, which includes fatty liver, steatohepatitis, hepatitis, cirrhosis, and hepatocellular tumors. Recent studies have found that ferroptosis is involved in the pathological development of non-viral liver diseases. Therefore, ferroptosis may be an ideal target for the treatment of non-viral liver diseases. In this review article, we will elaborate the molecular mechanism and regulatory mechanism of ferroptosis, explore the key role of ferroptosis in the Alcohol-related liver disease process, and summarize the existing targeted ferroptosis drugs and their feasibility for the treatment of Alcohol-related liver disease.

RESUMEN

Ferroptosis is a regulated cell death induced by iron-dependent lipid peroxidation. The heme-responsive transcription factor BTB and CNC homology 1 (BACH1) promotes ferroptosis by repressing the transcription of genes involved in glutathione (GSH) synthesis and intracellular labile iron metabolism, which are key regulatory pathways in ferroptosis. We found that BACH1 re-expression in Bach1-/- immortalized mouse embryonic fibroblasts (iMEFs) can induce ferroptosis upon 2-mercaptoethanol removal, without any ferroptosis inducers. In these iMEFs, GSH synthesis was reduced, and intracellular labile iron levels were increased upon BACH1 re-expression. We used this system to investigate whether the major ferroptosis regulators glutathione peroxidase 4 (Gpx4) and apoptosis-inducing factor mitochondria-associated 2 (Aifm2), the gene for ferroptosis suppressor protein 1, are target genes of BACH1. Neither Gpx4 nor Aifm2 was regulated by BACH1 in the iMEFs. However, we found that BACH1 represses AIFM2 transcription in human pancreatic cancer cells. These results suggest that the ferroptosis regulators targeted by BACH1 may vary across different cell types and animal species. Furthermore, we confirmed that the ferroptosis induced by BACH1 re-expression exhibited a propagating effect. BACH1 re-expression represents a new strategy for inducing ferroptosis after GPX4 or system Xc- suppression and is expected to contribute to future ferroptosis research.

Asunto(s)

RESUMEN

Ferroptosis is a type of regulated cell death characterized by intracellular accumulation of iron and reactive oxygen species, inhibition of system Xc-, glutathione depletion, nicotinamide adenine dinucleotide phosphate oxidation and lipid peroxidation. Since its discovery and characterization in 2012, many efforts have been made to reveal the underlying mechanisms, modulating compounds, and its involvement in disease pathways. Ferroptosis inducers include erastin, sorafenib, sulfasalazine and glutamate, which, by inhibiting system Xc-, prevent the import of cysteine into the cells. RSL3, statins, Ml162 and Ml210 induce ferroptosis by inhibiting glutathione peroxidase 4 (GPX4), which is responsible for preventing the formation of lipid peroxides, and FIN56 and withaferin trigger GPX4 degradation. On the other side, ferroptosis inhibitors include ferrostatin-1, liproxstatin-1, α-tocopherol, zileuton, FSP1, CoQ10 and BH4, which interrupt the lipid peroxidation cascade. Additionally, deferoxamine, deferiprone and N-acetylcysteine, by targeting other cellular pathways, have also been classified as ferroptosis inhibitors. Increased evidence has established the involvement of ferroptosis in distinct brain diseases, including Alzheimer's, Parkinson's and Huntington's diseases, amyotrophic lateral sclerosis, multiple sclerosis, and Friedreich's ataxia. Thus, a deep understanding of how ferroptosis contributes to these diseases, and how it can be modulated, can open a new window of opportunities for novel therapeutic strategies and targets. Other studies have shown a sensitivity of cancer cells with mutated RAS to ferroptosis induction and that chemotherapeutic agents and ferroptosis inducers synergize in tumor treatment. Thus, it is tempting to consider that ferroptosis may arise as a target mechanistic pathway for the treatment of brain tumors. Therefore, this work provides an up-to-date review on the molecular and cellular mechanisms of ferroptosis and their involvement in brain diseases. In addition, information on the main ferroptosis inducers and inhibitors and their molecular targets is also provided.

Asunto(s)

RESUMEN

Ferroptosis is a kind of iron-dependent regulatory necrosis characterized by the fatal accumulation of iron-dependent lipid peroxides in the plasma membrane and the final oxidative damage of the cell membrane. Morphologically, ferroptosis features high membrane density, decreased or disappeared cristae, rupture of the mitochondrial outer membrane, plasma membrane integrity loss, cytoplasmic swelling, and organelle swelling. Under physiological conditions, ferroptosis occurs through two major pathways, the extrinsic or transporter-dependent pathway and the intrinsic or enzyme-regulated pathway, triggered by a series of small molecules inside and outside the cell. At present, it is assumed that ferroptosis is mainly related to abnormal toxicity of iron, lipid peroxidation, and mitochondrial dysfunction. With more detailed studies, ferroptosis plays potential pathogenic roles in multisystem diseases as a pathological response, and targeted regulation of ferroptosis in treating ferroptosis-related diseases has broad prospects. In conclusion, it is of great clinical significance to further clarify the specific mechanism of ferroptosis and explore new strategies for ferroptosis regulation. The present review emphatically summarizes the latest mechanism of ferroptosis, focusing on the regulation mechanism and clinical application of ferroptosis inducers and inhibitors. We are devoted to providing new ideas for the further study of ferroptosis and the diagnosis and treatment of ferroptosis-related multisystem diseases.

Asunto(s)

RESUMEN

BACKGROUND: Ferroptosis holds promise as a potential tumor therapy by programming cell death with a hallmark of reactive oxygen species (ROS)-induced lipid peroxidation. However, vigorous energy metabolism may assist tumors to resist oxidative damage and thus weaken the effects of ferroptosis in tumor treatment. RESULTS: Herein, a bifunctional antitumor platform was constructed via coordinated interactions between metal ions and nucleotides to synergistically activate ferroptosis and interrupt energy metabolism for tumor therapy. The designed nanoparticles were composed of Fe2+/small interfering RNA (siRNA) as the core and polydopamine as the cloak, which responded to the tumor microenvironment with structural dissociation, thereby permitting tumor-specific Fe2+ and siRNA release. The over-loaded Fe2+ ions in the tumor cells then triggered ferroptosis, with hallmarks of lipid peroxidation and cellular glutathione peroxidase 4 (GPX4) down-regulation. Simultaneously, the released siRNA targeted and down-regulated glyceraldehyde-3-phosphate dehydrogenase (GAPDH) expression in the tumor to inhibit glycolytic pathway, which interfered with tumor energy metabolism and enhanced Fe2+-induced ferroptosis to kill tumor cells. CONCLUSIONS: This study presents a concise fabrication of a metal ion/nucleotide-based platform to integrate ferroptosis and energy metabolism intervention in one vehicle, thereby providing a promising combination modality for anticancer therapy.

Asunto(s)

RESUMEN

Patient outcomes from the current clinical cancer therapy remain still far from satisfactory. However, in recent years, several biomedical discoveries and nanotechnological innovations have been made, so there is an impetus to combine these with conventional treatments to improve patient experience and disease prognosis. Ferroptosis, a term first coined in 2012, is an iron-dependent regulated cell death (RCD) based on the production of reactive oxygen species (ROS) and the consequent oxidization of polyunsaturated fatty acids (PUFAs). Many nanomaterials that can induce ferroptosis have been explored for applications in cancer therapy. In this review, we summarize the recent developments in ferroptosis-based nanomaterials for cancer therapy and discuss the future of ferroptosis, nanomedicine, and cancer therapy.

RESUMEN

Ferroptosis is a new mode of cell death different from cell necrosis, autophagy, apoptosis, and pyroptosis, which depends on the accumulation of reactive oxygen species (ROS) caused by iron-mediated lipid peroxidation, exhibits cellular, molecular, and gene-level characteristics distinct from other cell deaths. Since ferroptosis discovery, it has become a new target for antitumor therapy actively explored by researchers. In this review, we provide an overview of the known mechanisms that regulate the sensitivity of cancer cells to ferroptosis and the research progress of ferroptosis-related drugs (western medicine, traditional Chinese medicine, and nanomedicine), as well as the relationship between ferroptosis and cancer treatment, tumor drug resistance, and antitumor immunotherapy.

Asunto(s)

RESUMEN

Ferroptosis is a newly discovered form of regulated cell death that is the nexus between metabolism, redox biology, and human health. Emerging evidence shows the potential of triggering ferroptosis for cancer therapy, particularly for eradicating aggressive malignancies that are resistant to traditional therapies. Recently, there has been a great deal of effort to design and develop anticancer drugs based on ferroptosis induction. Recent advances of ferroptosis-inducing agents at the intersection of chemistry, materials science, and cancer biology are presented. The basis of ferroptosis is summarized first to highlight the feasibility and characteristics of triggering ferroptosis for cancer therapy. A literature review of ferroptosis inducers (including small molecules and nanomaterials) is then presented to delineate their design, action mechanisms, and anticancer applications. Finally, some considerations for research on ferroptosis inducers are spotlighted, followed by a discussion on the challenges and future development directions of this burgeoning field.

Asunto(s)

RESUMEN

Ferroptosis is a new form of regulated cell death which is different from apoptosis, necrosis and autophagy, and results from iron-dependent lipidperoxide accumulation. Now, it is found that ferroptosis is involved in multiple physiological and pathological processes, such as cancer, arteriosclerosis, neurodegenerative diseases, diabetes, antiviral immune response, acute renal failure, hepatic and heart ischemia/reperfusion injury. On the one hand, it could be found the appropriate drugs to promote ferroptosis to clear cancer cells and virus infected cells, etc. On the other hand, we could inhibit ferroptosis to protect healthy cells. China has a wealth of traditional Chinese medicine resources. Chinese medicine contains a variety of active ingredients that regulate ferroptosis. Here, this paper reported the research of ferroptosis pathway, targets of its inducers and inhibitors that have been discovered, and the regulatory effects of the discovered Chinese herbs and its active ingredients on ferroptosis to help clinical and scientific research.

Asunto(s)

RESUMEN

Ferroptosis is a new form of regulated cell death which is different from apoptosis, necrosis and autophagy, and results from iron-dependent lipidperoxide accumulation. Now, it is found that ferroptosis is involved in multiple physiological and pathological processes, such as cancer, arteriosclerosis, neurodegenerative diseases, diabetes, antiviral immune response, acute renal failure, hepatic and heart ischemia/reperfusion injury. On the one hand, it could be found the appropriate drugs to promote ferroptosis to clear cancer cells and virus infected cells, etc. On the other hand, we could inhibit ferroptosis to protect healthy cells. China has a wealth of traditional Chinese medicine resources. Chinese medicine contains a variety of active ingredients that regulate ferroptosis. Here, this paper reported the research of ferroptosis pathway, targets of its inducers and inhibitors that have been discovered, and the regulatory effects of the discovered Chinese herbs and its active ingredients on ferroptosis to help clinical and scientific research.

Asunto(s)