Ferroptosis in cancer: From molecular mechanisms to therapeutic strategies

Signal Transduction and Targeted Therapy, Journal Year: 2024, Volume and Issue: 9(1)

Published: March 8, 2024

Ferroptosis is a non-apoptotic form of regulated cell death characterized by the lethal accumulation iron-dependent membrane-localized lipid peroxides. It acts as an innate tumor suppressor mechanism and participates in biological processes tumors. Intriguingly, mesenchymal dedifferentiated cancer cells, which are usually resistant to apoptosis traditional therapies, exquisitely vulnerable ferroptosis, further underscoring its potential treatment approach for cancers, especially refractory cancers. However, impact ferroptosis on extends beyond direct cytotoxic effect cells. induction not only inhibits but also promotes development due negative anticancer immunity. Thus, comprehensive understanding role crucial successful translation therapy from laboratory clinical applications. In this review, we provide overview recent advancements cancer, covering molecular mechanisms, functions, regulatory pathways, interactions with microenvironment. We summarize applications immunotherapy, radiotherapy, systemic therapy, well inhibition various conditions. finally discuss markers, current challenges future directions cancer.

Language: Английский

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Iron homeostasis and ferroptosis in human diseases: mechanisms and therapeutic prospects

Signal Transduction and Targeted Therapy, Journal Year: 2024, Volume and Issue: 9(1)

Published: Oct. 14, 2024

Iron, an essential mineral in the body, is involved numerous physiological processes, making maintenance of iron homeostasis crucial for overall health. Both overload and deficiency can cause various disorders human diseases. Ferroptosis, a form cell death dependent on iron, characterized by extensive peroxidation lipids. Unlike other kinds classical unprogrammed death, ferroptosis primarily linked to disruptions metabolism, lipid peroxidation, antioxidant system imbalance. Ferroptosis regulated through transcription, translation, post-translational modifications, which affect cellular sensitivity ferroptosis. Over past decade or so, diseases have been as part their etiology, including cancers, metabolic disorders, autoimmune diseases, central nervous cardiovascular musculoskeletal Ferroptosis-related proteins become attractive targets many major that are currently incurable, some regulators shown therapeutic effects clinical trials although further validation potential needed. Therefore, in-depth analysis its molecular mechanisms may offer additional strategies prevention treatment. In this review, we discuss significance contribution etiology development along with evidence supporting targeting approach. Importantly, evaluate recent promising interventions, providing guidance future targeted treatment therapies against

Language: Английский

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The mechanism of ferroptosis and its related diseases

Molecular Biomedicine, Journal Year: 2023, Volume and Issue: 4(1)

Published: Oct. 16, 2023

Abstract Ferroptosis, a regulated form of cellular death characterized by the iron-mediated accumulation lipid peroxides, provides novel avenue for delving into intersection metabolism, oxidative stress, and disease pathology. We have witnessed mounting fascination with ferroptosis, attributed to its pivotal roles across diverse physiological pathological conditions including developmental processes, metabolic dynamics, oncogenic pathways, neurodegenerative cascades, traumatic tissue injuries. By unraveling intricate underpinnings molecular machinery, contributors, signaling conduits, regulatory networks governing researchers aim bridge gap between intricacies this unique mode multifaceted implications health disease. In light rapidly advancing landscape ferroptosis research, we present comprehensive review aiming at extensive in origins progress human diseases. This concludes careful analysis potential treatment approaches carefully designed either inhibit or promote ferroptosis. Additionally, succinctly summarized therapeutic targets compounds that hold promise targeting within various facet underscores burgeoning possibilities manipulating as strategy. summary, enriched insights both investigators practitioners, while fostering an elevated comprehension latent translational utilities. revealing basic processes investigating possibilities, crucial resource scientists medical aiding deep understanding effects situations.

Language: Английский

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Ferroptosis: Emerging mechanisms, biological function, and therapeutic potential in cancer and inflammation

Cell Death Discovery, Journal Year: 2024, Volume and Issue: 10(1)

Published: Jan. 24, 2024

Abstract Ferroptosis represents a distinct form of programmed cell death triggered by excessive iron accumulation and lipid peroxidation-induced damage. This mode differentiates from classical in terms morphology biochemistry. stands out for its exceptional biological characteristics has garnered extensive research conversations as death. Its dysfunctional activation is closely linked to the onset diseases, particularly inflammation cancer, making ferroptosis promising avenue combating these conditions. As such, exploring may offer innovative approaches treating cancer inflammatory diseases. Our review provides insights into relevant regulatory mechanisms ferroptosis, examining impact ferroptosis-related factors both physiological pathological perspectives. Describing crosstalk between tumor- inflammation-associated signaling pathways potential inducers overcoming drug-resistant cancers are discussed, aiming inform further novel therapeutic directions relation

Language: Английский

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A Copper/Ferrous‐Engineering Redox Homeostasis Disruptor for Cuproptosis/Ferroptosis Co‐Activated Nanocatalytic Therapy in Liver Cancer

Advanced Functional Materials, Journal Year: 2024, Volume and Issue: 34(37)

Published: April 25, 2024

Abstract Cuproptosis and ferroptosis hold great promise for overcoming apoptotic resistance in liver cancer based on their unique metal‐driven cell death modalities. However, insufficient intracellular copper iron concentration, complicated tumor microenvironment (TME), unclear cross‐regulatory mechanisms between cuproptosis ferroptosis, severely restrict the therapeutic performance. Herein, copper‐doped hollow Prussian blue (CHP) nanozymes are rationally designed loading photosensitizer indocyanine green (ICG) O 2 ‐saturated perfluorohexane (PFH), denoted as ‐PFH@CHPI nanoparticles, to induce ferroptosis. In response specific TME, CHP can synergistically catalyze Fenton reactions consume endogenous glutathione, leading accumulation of reactive oxygen species. Upon near‐infrared irradiation, ‐PFH@CHPI‐enabled photothermal effect simultaneously accelerate catalytic trigger release photodynamic therapy promote oxidative stress. Notably, be effectively activated through Cu + ‐mediated dihydrolipoamide S‐acetyltransferase aggregation Fe–S cluster protein loss. Concurrently, tilt redox balance is favorable lipid peroxidation glutathione peroxidase 4 inactivation, resulting an augmented effect. Mechanistically, stress‐boosted jointly disrupt mitochondrial metabolism, which turn exacerbates stress, thus realizing a mutually enhanced This work may provide new guidance utilizing copper/ferrous‐engineering cuproptosis/ferroptosis synergetic therapy.

Language: Английский

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Chemical Design of Magnetic Nanomaterials for Imaging and Ferroptosis-Based Cancer Therapy

Chemical Reviews, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 14, 2025

Ferroptosis, an iron-dependent form of regulatory cell death, has garnered significant interest as a therapeutic target in cancer treatment due to its distinct characteristics, including lipid peroxide generation and redox imbalance. However, clinical application oncology is currently limited by issues such suboptimal efficacy potential off-target effects. The advent nanotechnology provided new way for overcoming these challenges through the development activatable magnetic nanoparticles (MNPs). These innovative MNPs are designed improve specificity ferroptosis induction. This Review delves into chemical biological principles guiding design ferroptosis-based therapies imaging-guided therapies. It discusses mechanisms attributes ferroptosis, composition MNPs, their mechanism action inducers, integration with advanced imaging techniques monitoring. Additionally, we examine convergence other strategies, chemodynamic therapy, photothermal photodynamic sonodynamic immunotherapy, within context nanomedicine strategies utilizing MNPs. highlights multifunctional surpass limitations conventional treatments, envisioning future drug-resistance-free, precision diagnostics treating recalcitrant cancers.

Language: Английский

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Enhanced Transcutaneous Chemodynamic Therapy for Melanoma Treatment through Cascaded Fenton-like Reactions and Nitric Oxide Delivery

ACS Nano, Journal Year: 2023, Volume and Issue: 17(16), P. 15713 - 15723

Published: Aug. 11, 2023

Chemodynamic therapy (CDT) has emerged as a promising strategy for cancer treatment. However, its effectiveness been hindered by insufficient hydrogen peroxide (H2O2) and high reductive glutathione (GSH) within tumors, which are the two main reasons inefficiency of Fenton/Fenton-like reaction-based CDT. Herein, we present H2O2 boost-GSH depletion enhanced CDT to fight against melanoma through microneedle (MN)-based transcutaneous delivery method. The MN system is composed dissolvable polyvinylpyrrolidone integrated with stimuli-responsive prodrugs. Under an intracellular acidic environment, smart release boosting components triggered, subsequently initiating nitric oxide (NO) enhancing Fenton-like reaction in cascade manner. generation hydroxyl radicals (•OH), along GSH NO, amplifies oxidative stress tumor cells, promoting apoptosis ferroptosis. antitumor efficacy patch validated A375 mouse model. This "H2O2 depletion-Fenton killing" expands options superficial treatment MN-mediated

Language: Английский

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Asymmetric Coordination of Iron Single‐Atom Nanozymes with Efficient Self‐Cascade Catalysis for Ferroptosis Therapy

Advanced Functional Materials, Journal Year: 2023, Volume and Issue: 34(14)

Published: Dec. 26, 2023

Abstract Single‐atom nanozymes (SAzymes) hold great promise in tumor therapy due to their maximized atomic utilization and well‐defined electronic structures. However, they still face challenges of activity, specificity, targeting that impede therapeutic efficacy. Herein, a practical strategy is reported construct asymmetric N, S‐coordinated Fe SAzymes (Fe‐S/N‐C). Benefiting from the regulatory influence S atoms on disruption local charge symmetry center atoms, Fe‐S/N‐C exhibit significantly enhanced peroxidase (POD)‐ glutathione oxidase (GSHOx)‐like activities, with catalytic efficiencies being 6.33 47.88 times higher than symmetric Fe‐N 4 counterparts, respectively. Theoretical calculations demonstrate interface configuration increases electron localization around sites, thus facilitating adsorption activation H 2 O . By camouflaging macrophage membranes, tumor‐targeting nanocatalytic agents (M@Fe‐S/N‐C) trigger self‐cascade catalysis microenvironment for ferroptosis‐based tumor‐specific therapy. These results open up promising avenue addressing limitations associated current SAzymes‐based therapies.

Language: Английский

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Imatinib induces ferroptosis in gastrointestinal stromal tumors by promoting STUB1-mediated GPX4 ubiquitination

Cell Death and Disease, Journal Year: 2023, Volume and Issue: 14(12)

Published: Dec. 18, 2023

Abstract Imatinib (IM) has significantly improved the prognosis of gastrointestinal stromal tumor (GIST) patients, but some patients still have primary resistance to IM, and approximately half develop acquired drug within 2 years treatment, necessitating exploration new treatment strategies. Targeting ferroptosis as a novel approach gained attention. Yet, there is limited research on in GIST, underlying mechanism remains unclear. In this study, we revealed that IM increased lipid reactive oxygen species intracellular Fe 2+ levels, decreased glutathione levels GIST. This effect could be partially inhibited by Ferrostatin-1. Additionally, knocking down STUB1 overexpressing GPX4 reversed IM-induced effect. Moreover, was identified E3 ubiquitin ligase GPX4, promoting ubiquitination at site K191 GPX4. The combination inhibitor RSL3 synergistically induces ferroptosis, inhibiting GIST proliferation both vivo vitro. Furthermore, expression serve independent prognostic factors for conclusion, study first demonstrate STUB1-mediated emerges promising therapeutic strategy

Language: Английский

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Mitochondria-Targeted Prodrug Nanoassemblies for Efficient Ferroptosis-Based Therapy via Devastating Ferroptosis Defense Systems

ACS Nano, Journal Year: 2024, Volume and Issue: 18(11), P. 7945 - 7958

Published: March 7, 2024

Ferroptosis is a form of regulated cell death accompanied by lipid reactive oxygen species (ROS) accumulation in an iron-dependent manner. However, the efficiency tumorous ferroptosis was seriously restricted intracellular defense systems, glutathione peroxidase 4 (GPX4) system, and ubiquinol (CoQH2) system. Inspired crucial role mitochondria process, we reported prodrug nanoassembly capable unleashing potent mitochondrial peroxidation ferroptotic death. Dihydroorotate dehydrogenase (DHODH) inhibitor (QA) combined with triphenylphosphonium moiety through disulfide-containing linker to engineer well-defined nanoassemblies (QSSP) within single-molecular framework. After being trapped cancer cells, acidic condition provoked structural disassembly QSSP liberate free molecules. The membrane-potential-driven lipophilic cation delivered explicitly into mitochondria. Afterward, thiol–disulfide exchange would occur downregulation reduced levels, thus resulting mitochondria-localized GPX4 inactivation for ferroptosis. Simultaneously, released QA from hydrolysis reaction adjacent ester bond could further devastate evoke robust via DHODH-CoQH2 This subcellular targeted provides reference designing ferroptosis-based strategy efficient therapy interfering antiferroptosis systems.

Language: Английский

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