Targeting ferroptosis opens new avenues for the development of novel therapeutics

Signal Transduction and Targeted Therapy, Journal Year: 2023, Volume and Issue: 8(1)

Published: Sept. 21, 2023

Abstract Ferroptosis is an iron-dependent form of regulated cell death with distinct characteristics, including altered iron homeostasis, reduced defense against oxidative stress, and abnormal lipid peroxidation. Recent studies have provided compelling evidence supporting the notion that ferroptosis plays a key pathogenic role in many diseases such as various cancer types, neurodegenerative disease, involving tissue and/or organ injury, inflammatory infectious diseases. Although precise regulatory networks underlie are largely unknown, particularly respect to initiation progression diseases, recognized bona fide target for further development treatment prevention strategies. Over past decade, considerable progress has been made developing pharmacological agonists antagonists these ferroptosis-related conditions. Here, we provide detailed overview our current knowledge regarding ferroptosis, its pathological roles, regulation during disease progression. Focusing on use chemical tools preclinical studies, also summarize recent advances targeting across growing spectrum ferroptosis-associated Finally, discuss new challenges opportunities potential strategy treating

Language: Английский

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NAC alleviative ferroptosis in diabetic nephropathy via maintaining mitochondrial redox homeostasis through activating SIRT3-SOD2/Gpx4 pathway

Free Radical Biology and Medicine, Journal Year: 2022, Volume and Issue: 187, P. 158 - 170

Published: May 31, 2022

Language: Английский

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Hydropersulfides Inhibit Lipid Peroxidation and Protect Cells from Ferroptosis

Journal of the American Chemical Society, Journal Year: 2022, Volume and Issue: 144(34), P. 15825 - 15837

Published: Aug. 17, 2022

Hydropersulfides (RSSH) are believed to serve important roles in vivo, including as scavengers of damaging oxidants and electrophiles. The α-effect makes RSSH not only much better nucleophiles than thiols (RSH), but also more potent H-atom transfer agents. Since HAT is the mechanism action most small-molecule inhibitors phospholipid peroxidation associated ferroptotic cell death, we have investigated their reactivity this context. Using fluorescence-enabled inhibited autoxidation (FENIX) approach, found be highly reactive toward phospholipid-derived peroxyl radicals (kinh = 2 × 105 M–1 s–1), equaling ferroptosis identified date. Related (poly)sulfide products resulting from rapid self-reaction under physiological conditions (e.g., disulfide, trisulfide, H2S) essentially unreactive, combinations which can produced situ (i.e., polysulfides with H2S or H2S2) effective. In generation designed precursors release via intramolecular substitution hydrolysis improve radical-trapping efficiency by minimizing deleterious self-reactions. A brief survey structure–reactivity relationships enabled design new that efficient. translates (phospho)lipid bilayers culture (mouse embryonic fibroblasts), where they were inhibit induced inactivation glutathione peroxidase-4 (GPX4) deletion gene encoding it. These results suggest pathways responsible for biosynthesis may act a suppression system alongside recently discovered FSP1/ubiquinone GCH1/BH4/DHFR systems.

Language: Английский

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The emerging role of ferroptosis in female reproductive disorders

Biomedicine & Pharmacotherapy, Journal Year: 2023, Volume and Issue: 166, P. 115415 - 115415

Published: Sept. 4, 2023

Iron, as an essential trace element for the organism, is vital maintaining organism's health. Excessive iron can promote reactive oxygen species (ROS) accumulation, thus damaging cells and tissues. Ferroptosis a novel form of programmed cell death distinguished by overload lipid peroxidation, which unique from autophagy, apoptosis necrosis, more studies are focusing on ferroptosis. Recent evidence suggests that ferroptosis associated with development female reproductive disorders (FRDs), including polycystic ovary syndrome (PCOS), premature ovarian insufficiency (POI), endometriosis (EMs), cancer (OC), preeclampsia (PE) spontaneous abortion (SA). Pathways genes may participate in processes regulate granulosa proliferation secretion, oocyte development, reserve function, early embryonic placental oxidative stress. However, its exact mechanism has not been fully revealed. Therefore, our review systematically elaborates occurrence research progress FRDs, view to providing literature references clinical targeting -related pathways regulatory factors management FRDs.

Language: Английский

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In defence of ferroptosis

Signal Transduction and Targeted Therapy, Journal Year: 2025, Volume and Issue: 10(1)

Published: Jan. 2, 2025

Abstract Rampant phospholipid peroxidation initiated by iron causes ferroptosis unless this is restrained cellular defences. Ferroptosis increasingly implicated in a host of diseases, and unlike other cell death programs the physiological initiation conceived to occur not an endogenous executioner, but withdrawal guardians that otherwise constantly oppose induction. Here, we profile key ferroptotic defence strategies including regulation, modulation enzymes metabolite systems: glutathione reductase (GR), suppressor protein 1 (FSP1), NAD(P)H Quinone Dehydrogenase (NQO1), Dihydrofolate (DHFR), retinal reductases dehydrogenases (RDH) thioredoxin (TR). A common thread uniting all metabolites combat lipid during dependence on reductant, nicotinamide adenine dinucleotide phosphate (NADPH). We will outline how cells control central carbon metabolism produce NADPH necessary precursors defend against ferroptosis. Subsequently discuss evidence for dysregulation different disease contexts glucose-6-phosphate dehydrogenase deficiency, cancer neurodegeneration. Finally, several anti-ferroptosis therapeutic spanning use radical trapping agents, dependent redox support highlight current landscape clinical trials focusing

Language: Английский

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G protein-coupled estrogen receptor activation by bisphenol-A disrupts lipid metabolism and induces ferroptosis in the liver

Environmental Pollution, Journal Year: 2023, Volume and Issue: 334, P. 122211 - 122211

Published: July 14, 2023

Language: Английский

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Mitochondrial Dysfunction in PCOS: Insights into Reproductive Organ Pathophysiology

International Journal of Molecular Sciences, Journal Year: 2023, Volume and Issue: 24(17), P. 13123 - 13123

Published: Aug. 23, 2023

Polycystic ovary syndrome (PCOS) is a complex, but relatively common endocrine disorder associated with chronic anovulation, hyperandrogenism, and micro-polycystic ovaries. In addition to reduced fertility, people PCOS have higher risk of obesity, insulin resistance, metabolic disease, all comorbidities that are mitochondrial dysfunction. This review summarizes human animal data report dysfunction dysregulation in better understand how mitochondria impact reproductive organ pathophysiology. in-depth considers the elements regulating quantity quality, from biogenesis under transcriptional regulation both nuclear genome ultrastructural functional complexes regulate cellular metabolism reactive oxygen species production, as well dynamics subcellular interactions key quality control. When any these functions disrupted, energetic equilibrium within cell changes, processes can fail, death occur. If this process ongoing, it affects tissue function, causing disease. The objective consolidate classify broad number studies various organs, including (oocytes granulosa cells), uterus, placenta, circulation, A secondary uncover potential role transgenerational transmission disorders.

Language: Английский

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Ovarian ferroptosis induced by androgen is involved in pathogenesis of PCOS

Human Reproduction Open, Journal Year: 2024, Volume and Issue: 2024(2)

Published: Jan. 1, 2024

Abstract STUDY QUESTION Does ovarian ferroptosis play an active role in the development of polycystic ovary syndrome (PCOS)? SUMMARY ANSWER Increased was present PCOS ovaries and inhibition with ferrostatin-1 (Fer-1) ameliorated morphology anovulation. WHAT IS KNOWN ALREADY Programmed cell death plays a fundamental follicle development. However, types mechanisms involved are yet to be elucidated. Ferroptosis is recently discovered iron-dependent programmed death. Impaired iron metabolism have been observed women PCOS, main cause anovulatory infertility. Additionally, previous studies reported that abnormal expression noncoding RNA may promote immortalized granulosa lines. little known about whether increased there insufficient direct evidence for underlying mechanism. Moreover, effect Fer-1 remains unclear. DESIGN, SIZE, DURATION evaluated human cells (hGCs) from non-PCOS (n = 6–16) 7–18) patients. The experimental study completed vitro using primary hGCs undergoing IVF. Improvements indicators following were investigated dehydroepiandrosterone (DHEA)-induced rat model 8 per group). PARTICIPANTS/MATERIALS, SETTING, METHODS Ovarian ways: by detecting concentrations via ELISA fluorescent probes; measuring malondialdehyde (MDA) ELISA; assessing ferroptosis-related protein abundance western blotting; observing mitochondrial transmission electron microscopy; determining viability. Primary collected They treated dihydrotestosterone (DHT) 24 h. DHT on examined presence or absence small interfering RNA-mediated knockdown putative receptor coregulator signaling molecules. progression explored vivo rats. DHEA-induced inhibitor, Fer-1, oocytes metaphase II counted after stimulation. rats inducer, RSL3, further explore ferroptosis. testosterone, FSH, LH assessed. MAIN RESULTS AND THE ROLE OF CHANCE detected patients PCOS. Fe2+ (P < 0.05) MDA 0.05), upregulated nuclear coactivator 4 levels, downregulated ferritin heavy chain 1 (FTH1) glutathione peroxidase (GPX4) proteins 0.05 versus control). shown induce activation NOCA4-dependent ferritinophagy. cluster traits including impaired glucose tolerance, irregular estrous cycles, reproductive hormone dysfunction, hyperandrogenism, ovaries, anovulation, oocyte quality 0.05). Treating RSL3 resulted hyperandrogenism LARGE-SCALE DATA N/A. LIMITATIONS, REASONS FOR CAUTION Although ovarian-targeted more targeted treatment cycle between require exploration. since shows high heterogeneity, it important investigate increases all WIDER IMPLICATIONS FINDINGS Androgen-induced appears pathogenesis which potentially makes promising target FUNDING/COMPETING INTEREST(S) This supported National Key R&D Program China (2023YFC2705500, 2023YFC2705505, 2019YFA0802604), Natural Science Foundation (No. 82130046, 82320108009, 82101708, 82101747, 82001517), Shanghai leading talent program, Innovative research team high-level local universities SHSMU-ZLCX20210201, No. SSMU-ZLCX20180401), Jiaotong University School Medicine, Affiliated Renji Hospital Clinical Research Innovation Cultivation Fund (RJPY-DZX-003) Municipal Education Commission—Gaofeng Medicine Grant Support 20161413), Shanghai’s Top Priority Center Construction Project (2023ZZ02002), Three-Year Action Plan Strengthening Public Health System (GWVI-11.1-36). authors report no competing interests.

Language: Английский

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Ellagic acid inhibits dihydrotestosterone-induced ferroptosis and promotes hair regeneration by activating the wnt/β-catenin signaling pathway

Journal of Ethnopharmacology, Journal Year: 2024, Volume and Issue: 330, P. 118227 - 118227

Published: April 28, 2024

Language: Английский

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Ferroptosis: mechanisms and therapeutic targets

MedComm, Journal Year: 2024, Volume and Issue: 5(12)

Published: Nov. 20, 2024

Ferroptosis is a nonapoptotic form of cell death characterized by iron-dependent lipid peroxidation in membrane phospholipids. Since its identification 2012, extensive research has unveiled involvement the pathophysiology numerous diseases, including cancers, neurodegenerative disorders, organ injuries, infectious autoimmune conditions, metabolic and skin diseases. Oxidizable lipids, overload iron, compromised antioxidant systems are known as critical prerequisites for driving overwhelming peroxidation, ultimately leading to plasma rupture ferroptotic death. However, precise regulatory networks governing ferroptosis ferroptosis-targeted therapy these diseases remain largely undefined, hindering development pharmacological agonists antagonists. In this review, we first elucidate core mechanisms summarize epigenetic modifications (e.g., histone modifications, DNA methylation, noncoding RNAs, N6-methyladenosine modification) nonepigenetic genetic mutations, transcriptional regulation, posttranslational modifications). We then discuss association between disease pathogenesis explore therapeutic approaches targeting ferroptosis. also introduce potential clinical monitoring strategies Finally, put forward several unresolved issues which progress needed better understand hope review will offer promise application therapies context human health disease.

Language: Английский

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