Ferroptosis in health and disease

Redox Biology, Journal Year: 2024, Volume and Issue: 75, P. 103211 - 103211

Published: May 30, 2024

Ferroptosis is a pervasive non-apoptotic form of cell death highly relevant in various degenerative diseases and malignancies. The hallmark ferroptosis uncontrolled overwhelming peroxidation polyunsaturated fatty acids contained membrane phospholipids, which eventually leads to rupture the plasma membrane. unique that it essentially spontaneous, uncatalyzed chemical process based on perturbed iron redox homeostasis contributing process, but nonetheless modulated by many metabolic nodes impinge cells' susceptibility ferroptosis. Among affecting sensitivity, several have emerged as promising candidates for pharmacological intervention, rendering ferroptosis-related proteins attractive targets treatment numerous currently incurable diseases. Herein, current members Germany-wide research consortium focusing research, well key external experts who made seminal contributions this rapidly growing exciting field gathered provide comprehensive, state-of-the-art review Specific topics include: basic mechanisms, vivo relevance, specialized methodologies, tools, potential contribution disease etiopathology progression. We hope article will not only established scientists newcomers with an overview multiple facets ferroptosis, also encourage additional efforts characterize further molecular pathways modulating ultimate goal develop novel pharmacotherapies tackle associated - or caused

Language: Английский

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Advances in research on immunocyte iron metabolism, ferroptosis, and their regulatory roles in autoimmune and autoinflammatory diseases

Cell Death and Disease, Journal Year: 2024, Volume and Issue: 15(7)

Published: July 4, 2024

Abstract Autoimmune diseases commonly affect various systems, but their etiology and pathogenesis remain unclear. Currently, increasing research has highlighted the role of ferroptosis in immune regulation, with cells being a crucial component body’s system. This review provides an overview discusses relationship between ferroptosis, programmed cell death cells, autoimmune diseases. Additionally, it summarizes key targets such as GPX4 TFR, responses. Furthermore, release multiple molecules, including damage-associated molecular patterns (DAMPs), following by is examined, these molecules further influence differentiation function thereby affecting occurrence progression Moreover, secrete factors or metabolites, which also impact target organs tissues involved Iron chelators, chloroquine its derivatives, antioxidants, calreticulin have been demonstrated to be effective animal studies for certain diseases, exerting anti-inflammatory immunomodulatory effects. Finally, brief summary future perspectives on are provided, aiming guide disease treatment strategies.

Language: Английский

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Increased melanin induces aberrant keratinocyte − melanocyte − basal − fibroblast cell communication and fibrogenesis by inducing iron overload and ferroptosis resistance in keloids

Cell Communication and Signaling, Journal Year: 2025, Volume and Issue: 23(1)

Published: March 18, 2025

Keloid is a typical skin fibrotic disease with unclear mechanisms and limited therapeutic options. Fibroblast-induced fibrogenesis crucial cause of KD. However, the types cells involved in fibroblast KD specific are unclear. This study aimed to investigate role melanocyte-secreted melanin promoting its mechanism evaluate potential effect intervening treating keloid. The activity pigmentation-related pathways melanocytes was examined using single-cell RNA-sequence (scRNA-seq) analysis. Masson-Fontana staining or isolated quantification detected levels distribution cells. Collagen deposition, wounding healing, proliferation analysis were employed integratively assess fibrogenesis. After treatment, bulk-seq identified fibroblasts' differentially expressed genes (DEGs). iron by Perl's quantification. Cell viability, LipidROS, malondialdehyde assay accessed ferroptosis levels. ML329 evaluated keloid-bearing mice. We found enriched keloid further validated increased patients. Additionally, positively correlated Area Severity Index Furthermore, significantly promoted proliferation, migration, collagen synthesis. Mechanically, basal cell permeability inflammation facilitate transfer dermis, where it activated fibroblasts evoking overload resistance. Consistently, resistance primary tissues Inhibition effectively diminish melanin-induced Interestingly, induced an autocrine manner stimulated keratinocytes take up deepen color upregulating F2R-like trypsin receptor 1 (F2RL1). In vivo, delivery ML329, microphthalmia-associated transcription factor (MITF) inhibitor, could suppress melanogenesis alleviate human nude Meanwhile, decreased content restored sensitivities ferroptosis. Collectively, melanin-lowing strategies may appear as new target for Current treatments ineffective. Our research demonstrates that increase patients play significant progression mediating aberrant keratinocyte − melanocyte crosstalk. Importantly, we pharmacological inhibition MITF shows promise alleviating keloid, offering breakthrough treatment. synthesis pathway abnormally melanocytes. Melanin destroys membrane barrier triggering translocates dermal layers paracrine induce overgrowth, ECM deposition inducing maintains melanocytes' hyperproliferative non-immortal properties manner. It enhances keratocyte PAR-2 promote transit superficial epidermis layers, which be related deepening color. alleviates

Language: Английский

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Gasdermin E promotes translocation of p65 and c-jun into nucleus in keratinocytes for progression of psoriatic skin inflammation

Cell Death and Disease, Journal Year: 2024, Volume and Issue: 15(3)

Published: March 1, 2024

Abstract Gasdermin E (GSDME) has recently been identified as a critical executioner to mediate pyroptosis. While epidermal keratinocytes can initiate GSDME-mediated pyroptosis, the role of keratinocyte GSDME in psoriatic dermatitis remains poorly characterized. Through analysis GEO datasets, we found elevated levels lesional skin. Additionally, correlated with both psoriasis severity and response biologics treatments. Single-cell RNA sequencing (scRNA-seq) from dataset revealed upregulation patients. In imiquimod (IMQ)-induced psoriasis-like mouse model, full-length cleaved forms caspase-3 were epidermis. Abnormal proliferation differentiation attenuated Gsdme -/- mice keratinocyte-specific conditional knockout after IMQ stimulation. Exposure mixed cytokines (M5), mimicking conditions, led cleavage. Moreover, interaction between GSDME-FL p65 or c-jun was significantly increased M5 knockdown inhibited nuclear translocation decreased inflammatory mediators such IL1β, CCL20, CXCL1, CXCL8, S100A8, S100A9 M5-challenged keratinocytes. conclusion, contributes pathogenesis progression psoriasis, potentially pyroptosis-independent manner by interacting promoting c-jun. These findings suggest that could serve potential therapeutic target for treatment.

Language: Английский

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Molecular and therapeutic landscape of ferroptosis in skin diseases

Chinese Medical Journal, Journal Year: 2024, Volume and Issue: 137(15), P. 1777 - 1789

Published: July 8, 2024

Regulated cell death (RCD) is a critical physiological process essential in maintaining skin homeostasis. Among the various forms of RCD, ferroptosis stands out due to its distinct features iron accumulation, lipid peroxidation, and involvement inhibitory antioxidant systems. In recent years, an expanding body research has solidly linked emergence disorders. Therefore, understanding mechanisms underlying diseases crucial for advancing therapy prevention strategies. This review commences with succinct elucidation that underpin ferroptosis, embarks on thorough exploration ferroptosis's role across spectrum conditions, encompassing melanoma, psoriasis, systemic lupus erythematosus (SLE), vitiligo, dermatological ailments precipitated by ultraviolet (UV) exposure, scrutinizes potential therapeutic benefits pharmacological interventions aimed at modulating amelioration diseases.

Language: Английский

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Bioactive lipids in the skin barrier mediate its functionality in health and disease

Pharmacology & Therapeutics, Journal Year: 2024, Volume and Issue: 260, P. 108681 - 108681

Published: June 17, 2024

Our skin protects us from external threats including ultraviolet radiation, pathogens and chemicals, prevents excessive trans-epidermal water loss. These varied activities are reliant on a vast array of lipids, many which unique to skin, that support physical, microbiological immunological barriers. The cutaneous physical barrier is dependent specific lipid matrix surrounds terminally-differentiated keratinocytes in the stratum corneum. Sebum- keratinocyte-derived lipids cover skin's surface regulate microbiota. Meanwhile, signal between resident infiltrating immune cells, driving inflammation its resolution response other threats. Lipids particular importance include ceramides, crucial for corneum formation therefore functionality, fatty acids, contribute acidic pH microbiota, as well matrix, bioactive metabolites these involved cell signalling, inflammation, numerous processes. diverse complex maintain homeostasis healthy implicated diseases, unrelated systemic conditions with manifestations, processes such ageing. also gut-skin axis, signalling two sites. Therefore, provide valuable resource exploration processes, local disease development progression, accessible biomarker discovery disease, an opportunity fully understand relationship host Investigation could diagnostic prognostic biomarkers, help identify new targets interventions. Development improvement existing vitro silico approaches explore lipidome, advances lipidomics technologies, will facilitate ongoing progress research.

Language: Английский

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Metabolic influences on T cell in psoriasis: a literature review

Frontiers in Immunology, Journal Year: 2023, Volume and Issue: 14

Published: Nov. 15, 2023

Psoriasis is a systemic inflammatory disease that frequently coexists with various other conditions, such as essential hypertension, diabetes, metabolic syndrome, and bowel disease. The association between these diseases may be attributed to shared pathways abnormal immunomodulatory mechanisms. Furthermore, metabolites also play regulatory role in the function of different immune cells involved psoriasis pathogenesis, particularly T lymphocytes. In this review, we have summarized current research progress on cell metabolism psoriasis, encompassing regulation glucose metabolism, lipid amino acid within affected by psoriasis. We will explore interaction mechanism psoriatic cells. Moreover, further discussed metabolomics gain deeper understanding its pathogenesis identify potential new therapeutic targets through identification biomarkers associated condition.

Language: Английский

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Exploration of ferroptosis and necroptosis-related genes and potential molecular mechanisms in psoriasis and atherosclerosis

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

Published: July 12, 2024

Objective Ferroptosis and necroptosis are two recently identified forms of non-apoptotic cell death. Their dysregulation plays a critical role in the development progression Psoriasis (PsD) Atherosclerosis (AS). This study explores shared necroptosis-related genes elucidates their molecular mechanisms PsD AS through analysis public databases. Methods Data sets for (GSE30999) (GSE28829) were retrieved from GEO database. Differential gene expression (DEG) weighted co-expression network (WGCNA) performed. Machine learning algorithms candidate biomarkers, whose diagnostic values assessed using Receiver Operating Characteristic (ROC) curve analysis. Additionally, levels these biomarkers models quantitatively measured Western Blot (WB) real-time quantitative PCR (RT-qPCR). Furthermore, CIBERSORT evaluated immune infiltration tissues, highlighting correlation between characteristic cells. Predictive drugs targeting was conducted DGIdb database, an lncRNA-miRNA-mRNA related to constructed. Results We 44 differentially expressed ferroptosis-related (DE-FRGs) 30 (DE-NRGs). GO KEGG enrichment analyses revealed significant immune-related inflammatory pathways, especially NOD-like receptor TNF signaling pathways. Two (NAMPT, ZFP36) eight (C7, CARD6, CASP1, CTSD, HMOX1, NOD2, PYCARD, TNFRSF21) showed high sensitivity specificity ROC These findings corroborated external validation datasets models. Immune increased T cells gamma delta, Macrophages M0, M2 samples. we 43 5 genes. Notably, XIST-miR-93–5p-ZFP36/HMOX1 NEAT1-miR-93–5p-ZFP36/HMOX1 pathways have been as promising RNA regulatory PsD. Conclusion The potential key AS. significantly influence pathogenesis by modulating macrophage activity, participating regulation, mediating responses.

Language: Английский

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Targeting LINC00707 by vitamin D3 attenuates nitrogen mustard-caused dermal toxicity through inhibiting ferroptosis

Redox Biology, Journal Year: 2025, Volume and Issue: unknown, P. 103628 - 103628

Published: April 1, 2025

Nitrogen mustard (NM) causes severe skin injury that is lack of effective and targeted therapies. Vitamin D3 (VD3) emerges as a promising treatment option for NM-caused dermal toxicity; however, the underlying mechanisms are currently unclear. Herein, we identified NM markedly promoted ferroptosis by measurement decreased cell viability, glutathione, glutathione peroxidase 4 solute carrier family 7 member 11 levels, increased ROS, lipid iron/Fe2+ malondialdehyde contents in vitro vivo. Ferrostin-1 (Fer-1, inhibitor) attenuated death keratinocytes. Meanwhile, significantly inhibited phosphorylation AKT1 glycogen synthase kinase 3β (GSK3β) nuclear factor erythroid 2-related 2 (Nrf2) translocation, LINC00707 expression. Furthermore, NM-induced keratinocytes was abolished with agonists Nrf2 (tBHQ) (SC79), inhibitor GSK3β (AR-A014418), overexpression or knockdown. Mechanistically, directly bound protein domain suppressed its activated thereby inactivating Nrf2, subsequently inducing NM-treated Moreover, VD3 notably expression, inactivated GSK3β, translocation cytotoxicity induced The protective effects against toxicity were blocked erastin (a inducer), siRNA, enhanced knockdown Fer-1 In conclusion, ameliorated inhibiting ferroptosis, which partially mediated through LINC00707-AKT1-GSK3β-Nrf2 signaling pathway.

Language: Английский

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How Cells Die in Psoriasis?

International Journal of Molecular Sciences, Journal Year: 2025, Volume and Issue: 26(8), P. 3747 - 3747

Published: April 16, 2025

Psoriasis, a chronic immune-mediated inflammatory skin disorder characterized by keratinocyte hyperproliferation and cell infiltration, involves multiple distinct programmed death pathways in its pathogenesis. Following the Nomenclature Committee on Cell Death recommendations, we analyzed current literature examining diverse modes of cellular psoriatic lesions, with particular focus patterns their molecular signatures. Analysis revealed several mechanisms: autophagy dysfunction through IL-17A pathways, decreased apoptotic activity lesional skin, medication targeting anoikis psoriasis, upregulated necroptosis mediated RIPK1/MLKL signaling, gasdermin-mediated pyroptosis enhanced IL-1β secretion, coordinated PANoptotic activation specialized complexes, PARP1-mediated parthanatos promoting cutaneous inflammation, iron-dependent ferroptosis correlating Th22/Th17 responses, copper-dependent cuproptosis elevated MTF1/ATP7B/SLC31A1 expression, NETosis amplifying immune responses interaction Th17 axis. The intricate interplay between these mechanisms has led to development targeted therapeutic strategies, including mTOR inhibitors for modulation, RIPK1 necroptosis, various approaches NETosis, providing new directions more effective psoriasis treatments.

Language: Английский

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