Molecular mechanisms of ferroptosis and their involvement in brain diseases

Pharmacology & Therapeutics, Journal Year: 2023, Volume and Issue: 244, P. 108373 - 108373

Published: March 8, 2023

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

Language: Английский

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Beyond ferrostatin-1: a comprehensive review of ferroptosis inhibitors

Trends in Pharmacological Sciences, Journal Year: 2023, Volume and Issue: 44(12), P. 902 - 916

Published: Sept. 26, 2023

Ferroptosis is an iron-catalysed form of regulated cell death, which critically dependent on phospholipid peroxidation cellular membranes. Ferrostatin 1 was one the first synthetic radical-trapping antioxidants (RTAs) reported to block ferroptosis and it widely used as reference compound. has been linked multiple diseases use its inhibitors could have therapeutic potential. Although, novel biochemical pathways provide insights for different pharmacological targets, lipophilic RTAs remains superior. In this Review, we a comprehensive overview classes inhibitors, focusing endogenous RTAs. A thorough analysis their chemical, pharmacokinetic, properties potential in vivo provided.

Language: Английский

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GPX4, ferroptosis, and diseases

Biomedicine & Pharmacotherapy, Journal Year: 2024, Volume and Issue: 174, P. 116512 - 116512

Published: April 3, 2024

GPX4 (Glutathione peroxidase 4) serves as a crucial intracellular regulatory factor, participating in various physiological processes and playing significant role maintaining the redox homeostasis within body. Ferroptosis, form of iron-dependent non-apoptotic cell death, has gained considerable attention recent years due to its involvement multiple pathological processes. is closely associated with ferroptosis functions primary inhibitor this process. Together, contribute pathophysiology several diseases, including sepsis, nervous system ischemia reperfusion injury, cardiovascular cancer. This review comprehensively explores roles impacts development progression these aim providing insights for identifying potential therapeutic strategies future.

Language: Английский

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Metals in Cancer Research: Beyond Platinum Metallodrugs

ACS Central Science, Journal Year: 2024, Volume and Issue: 10(2), P. 242 - 250

Published: Feb. 7, 2024

The discovery of the medicinal properties platinum complexes has fueled design and synthesis new anticancer metallodrugs endowed with unique modes action (MoA). Among various families experimental antiproliferative agents, organometallics have emerged as ideal platforms to control compounds' reactivity stability in a physiological environment. This is advantageous efficiently deliver novel prodrug activation strategies, well acting only via noncovalent interactions their pharmacological targets. Noteworthy, another justification for advance organometallic compounds therapy stems from ability catalyze bioorthogonal reactions cancer cells. When not yet drug leads, such can be used selective chemical tools that benefit advantages catalytic amplification either label target interest (e.g., proteins) or boost output biochemical signals. Examples so-called "catalysis cells" are considered this Outlook together other candidates. selected case studies discussed frame more general challenges field inorganic chemistry.

Language: Английский

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Sperm freezing damage: the role of regulated cell death

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

Published: May 18, 2024

Abstract Substantial progress in research on sperm cryopreservation has occurred since the twentieth century, especially focusing improving freezing procedures and optimizing semen extenders. However, cellular biological mechanisms of damage are still unclear, which greatly restricts promotion development cryopreservation. An essential component is occurrence cell death. Considering existence multiple types death pathways, this review discusses connections between characteristics regulated (e.g., apoptosis ferroptosis), accidental intracellular ice crystals) with explores possible future directions field.

Language: Английский

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Ferroptosis inhibitors: past, present and future

Frontiers in Pharmacology, Journal Year: 2024, Volume and Issue: 15

Published: May 23, 2024

Ferroptosis is a non-apoptotic mode of programmed cell death characterized by iron dependence and lipid peroxidation. Since the ferroptosis was proposed, researchers have revealed mechanisms its formation continue to explore effective inhibitors in disease. Recent studies shown correlation between pathological neurodegenerative diseases, as well diseases involving tissue or organ damage. Acting on ferroptosis-related targets may provide new strategies for treatment ferroptosis-mediated diseases. This article specifically describes metabolic pathways summarizes reported action natural synthetic small molecule their efficacy The paper also treatments such gene therapy, nanotechnology, summarises challenges encountered clinical translation inhibitors. Finally, relationship other modes discussed, hopefully paving way future drug design discovery.

Language: Английский

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Progress and Challenges in Tumor Ferroptosis Treatment Strategies: A Comprehensive Review of Metal Complexes and Nanomedicine

Small, Journal Year: 2024, Volume and Issue: 20(25)

Published: Jan. 14, 2024

Abstract Ferroptosis is a new form of regulated cell death featuring iron‐dependent lipid peroxides accumulation to kill tumor cells. A growing body evidence has shown the potential ferroptosis‐based cancer therapy in eradicating refractory malignancies that are resistant apoptosis‐based conventional therapies. In recent years, studies have reported number ferroptosis inducers can increase vulnerability cells by regulating ferroptosis‐related signaling pathways. Encouraged rapid development ferroptosis‐driven therapies, interdisciplinary fields combine ferroptosis, pharmaceutical chemistry, and nanotechnology focused. First, prerequisites metabolic pathways for briefly introduced. Then, detail emerging designed boost ferroptosis‐induced therapy, including metal complexes, metal‐based nanoparticles, metal‐free nanoparticles summarized. Subsequently, application synergistic strategies with apoptosis other emphasis on use both cuproptosis induce redox dysregulation intracellular bimetallic copper/iron metabolism disorders during treatment discussed. Finally, challenges associated clinical translation future directions potentiating therapies highlighted.

Language: Английский

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Augmented ERO1α upon mTORC1 activation induces ferroptosis resistance and tumor progression via upregulation of SLC7A11

Journal of Experimental & Clinical Cancer Research, Journal Year: 2024, Volume and Issue: 43(1)

Published: April 13, 2024

The dysregulated mechanistic target of rapamycin complex 1 (mTORC1) signaling plays a critical role in ferroptosis resistance and tumorigenesis. However, the precise underlying mechanisms still need to be fully understood. Endoplasmic reticulum oxidoreductase alpha (ERO1α) expression mTORC1-activated mouse embryonic fibroblasts, cancer cells, laryngeal squamous cell carcinoma (LSCC) clinical samples was examined by quantitative real-time PCR (qRT-PCR), western blotting, immunofluorescence (IF), immunohistochemistry. Extensive vitro vivo experiments were carried out determine ERO1α its downstream target, member 11 solute carrier family 7 (SLC7A11), mTORC1-mediated proliferation, angiogenesis, resistance, tumor growth. regulatory mechanism on SLC7A11 investigated via RNA-sequencing, cytokine array, an enzyme-linked immunosorbent assay, qRT-PCR, IF, luciferase reporter chromatin immunoprecipitation assay. combined therapeutic effect inhibition inducer imidazole ketone erastin (IKE) cells evaluated using line-derived xenografts, LSCC organoids, patient-derived xenograft models. is functional mTORC1. Elevated induced exerted pro-oncogenic roles upregulation SLC7A11. Mechanically, stimulated transcription activating interleukin-6 (IL-6)/signal transducer activator 3 (STAT3) pathway. Moreover, with treatment IKE exhibited synergistic antitumor effects tumors. ERO1α/IL-6/STAT3/SLC7A11 pathway crucial for growth, combining inducers novel effective mTORC1-related

Language: Английский

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Oxidative Stress and Reprogramming of Lipid Metabolism in Cancers

Antioxidants, Journal Year: 2025, Volume and Issue: 14(2), P. 201 - 201

Published: Feb. 10, 2025

Oxidative stress is a common event involved in cancer pathophysiology, frequently accompanied by unique lipid metabolic reprogramming phenomena. caused mainly an imbalance between the production of reactive oxygen species (ROS) and antioxidant system cells. Emerging evidence has reported that oxidative regulates expression activity metabolism-related enzymes, leading to alteration cellular metabolism; this involves significant increase fatty acid synthesis shift way which lipids are taken up utilized. The dysregulation metabolism provides abundant intermediates synthesize biological macromolecules for rapid proliferation cells; moreover, it contributes maintenance intracellular redox homeostasis producing variety reducing agents. Moreover, derivatives metabolites play critical roles signal transduction within cells tumor microenvironment evades immune destruction facilitates invasion metastasis. These findings suggest close relationship during malignant progression cancers. This review focuses on crosstalk reprogramming, in-depth insight into modulation ROS cancers discusses potential strategies targeting therapy.

Language: Английский

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Visualizing Endoplasmic Reticulum Stress and Autophagy in Alzheimer’s Model Cells by a Peroxynitrite-Responsive AIEgen Fluorescent Probe

ACS Chemical Neuroscience, Journal Year: 2025, Volume and Issue: 16(2), P. 223 - 231

Published: Jan. 7, 2025

Endoplasmic reticulum (ER) stress and autophagy (ER-phagy) occurring in nerve cells are crucial physiological processes closely associated with Alzheimer's disease (AD). Visualizing the two is paramount to advance our understanding of AD pathologies. Among biomarkers identified, peroxynitrite (ONOO-) emerges as a key molecule initiation aggravation ER ER-phagy, highlighting its significance underlying mechanisms processes. In this work, we designed synthesized an innovative ONOO--responsive AIEgen-based fluorescent probe (DHQM) ability monitor ER-phagy model cells. DHQM demonstrated excellent aggregation-induced emission (AIE) properties, endowing it outstanding for washing-free intracellular imaging. Meanwhile, exhibited high sensitivity, remarkable selectivity ONOO-, exceptional ER-targeting ability. The was successfully applied fluorescence imaging ONOO- fluctuations assess status aluminum-induced Our findings revealed that ferroptosis, regulated cell death process, pivotal excessive production, which turn activated exacerbated stress. Furthermore, aluminum-stimulated observed utilizing DHQM, might be inhibiting ferroptosis mitigating aberrant Overall, study not only offers valuable insights into pathological at level but also opens new potential therapeutic avenues targeting these pathways.

Language: Английский

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