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

Signal Transduction and Targeted Therapy, Год журнала: 2024, Номер 9(1)

Опубликована: Окт. 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

Язык: Английский

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The gut microbiota metabolite capsiate regulate SLC2A1 expression by targeting HIF‐1α to inhibit knee osteoarthritis‐induced ferroptosis

Aging Cell, Год журнала: 2023, Номер 22(6)

Опубликована: Март 8, 2023

Abstract Ferroptosis is an iron‐dependent cell death that has been found to aggravate the progression of osteoarthritis (OA) and gut microbiota‐ OA axis refers bidirectional information network between microbiota OA, which may provide a new way protect OA. However, role microbiota‐derived metabolites in ferroptosis‐relative remains unclear. The objective this study was analyze protective effect its metabolite capsiate (CAT) on vivo vitro experiments. From June 2021 February 2022, 78 patients were evaluated retrospectively divided into two groups: health group ( n = 39) 40). Iron oxidative stress indicators determined peripheral blood samples. And then experiments, surgically destabilized medial meniscus (DMM) mice model established treated with CAT or Ferric Inhibitor‐1 (Fer‐1). Solute Carrier Family 2 Member 1 (SLC2A1) short hairpin RNA (shRNA) utilized inhibit SLC2A1 expression. Serum iron increased significantly but total binding capacity decreased than healthy people p < 0.0001). least absolute shrinkage selection operator clinical prediction suggested serum iron, capacity, transferrin, superoxide dismutase all independent predictors 0.001). Bioinformatics results SLC2A1, Metastasis‐Associated Lung Adenocarcinoma Transcript (MALAT1), HIF‐1α (Hypoxia Inducible Factor Alpha)‐related signaling pathways play important homeostasis In addition, 16s sequencing untargeted metabolomics used find negatively correlated Osteoarthritis Research Society International (OARSI) scores for chondrogenic degeneration 0.0017). Moreover, reduced ferroptosis‐dependent vitro. against could be eliminated by silencing SLC2A1. upregulated levels DMM group. HIF‐1α, MALAT1, apoptosis after knockout chondrocyte cells Finally, downregulation expression Adeno‐associated Virus (AAV) ‐SLC2A1 shRNA improves vivo. Our findings indicated inhibited HIF‐1a activating

Язык: Английский

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Inflammation Triggers Chondrocyte Ferroptosis in TMJOA via HIF-1α/TFRC

Journal of Dental Research, Год журнала: 2024, Номер 103(7), С. 712 - 722

Опубликована: Май 20, 2024

Inflammation and loss of articular cartilage are considered the major cause temporomandibular joint osteoarthritis (TMJOA), a painful condition (TMJ). To determine TMJ in these patients, synovial fluid TMJOA patients was compared prior to after hyaluronic lavage, revealing substantially elevated levels interleukin (IL) 1β, reactive oxidative stress (ROS), an overload Fe

Язык: Английский

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Antioxidant taurine inhibits chondrocyte ferroptosis through upregulation of OGT/Gpx4 signaling in osteoarthritis induced by anterior cruciate ligament transection

Journal of Advanced Research, Год журнала: 2025, Номер unknown

Опубликована: Янв. 1, 2025

The aim of this study was to investigate the potential molecular mechanisms by which taurine protects against cartilage degeneration. anterior cruciate ligament transection (ACLT) surgery used construct an animal model osteoarthritis (OA). Metabolomics identify characteristic metabolites in osteoarthritic chondrocytes. Transcriptomics and metabolomics were explore small molecule metabolite inflammatory chondrocyte damage. Cell transfection inhibitors/agonists validate chondrocytes vitro. Finally, adeno-associated virus degeneration vivo. Metabolomic assays identified as a possible key metabolic progression OA. revealed that O-GlcNAc transferase (OGT)-dependent O-GlcNAcylation Gpx4-dependent ferroptosis may mediate protective effects on chondrocytes, further confirmed gain loss function Subsequently, experiments indicated existence direct binding site for Gpx4 OGT proteins, provides evidence presence modification protein. Finnaly, we demonstrated OGT-dependent be Antioxidant inhibits through upregulation OGT/Gpx4 signaling. Supplementation with taurine, safe nonessential amino acid, therapeutic strategy

Язык: Английский

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Promotion of healthy aging through the nexus of gut microbiota and dietary phytochemicals

Advances in Nutrition, Год журнала: 2025, Номер unknown, С. 100376 - 100376

Опубликована: Янв. 1, 2025

Aging is associated with the decline of tissue and cellular functions, which can promote development age-related diseases like cancer, cardiovascular disease, neurodegeneration, disorders musculoskeletal immune systems. Healthspan length time an individual in good health free from chronic disabilities aging. Two modifiable factors that influence healthspan, healthy aging, prevent diseases, are diet microbiota gastrointestinal tract (gut microbiota). This review will discuss how dietary phytochemicals gut work concert to a First overview provided influences aging through its impact on barrier integrity, function, mitochondria function oxidative stress. Next, mechanisms by effect health, inflammation, nurture diverse microbial composition discussed. Lastly, directly producing bioactive metabolites food urolithin A, equol, hesperetin sulforaphane. These other phytochemical derived may healthspan Importantly, individual's capacity produce promoting cruciferous vegetables, berries, nuts, citrus soy products be dependent specific bacteria present gut.

Язык: Английский

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The role of HIF-1α in hypoxic metabolic reprogramming in osteoarthritis

Pharmacological Research, Год журнала: 2025, Номер unknown, С. 107649 - 107649

Опубликована: Фев. 1, 2025

The joint dysfunction caused by osteoarthritis (OA) is increasingly becoming a major challenge in global healthcare, and there currently no effective strategy to prevent the progression of OA. Therefore, better elucidating relevant mechanisms OA occurrence development will provide theoretical basis for formulating new prevention control strategies. Due long-term exposure cartilage tissue hypoxic microenvironment joints, metabolic reprogramming changes occur. Hypoxia-inducible factor-1alpha (HIF-1α), as core gene regulating hypoxia response vivo, plays an important regulatory role metabolism chondrocytes. HIF-1α adapts such glycolysis, oxidative phosphorylation (OXPHOS), amino acid metabolism, lipid In addition, also regulates macrophage polarization synovial inflammation, chondrocytes degeneration extracellular matrix (ECM) degradation, subchondral bone remodeling angiogenesis OA, affects pathophysiological Consequently, regulation has become therapeutic target this article reviews mechanism affecting chondrocyte reprogramming, focusing on summarizes potential ingredients or targets targeting order more beneficial treatment clinical drugs.

Язык: Английский

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The influence of microbiota on ferroptosis in intestinal diseases

Gut Microbes, Год журнала: 2023, Номер 15(2)

Опубликована: Окт. 5, 2023

Ferroptosis is a distinctive form of iron-dependent necrotic cell death, characterized by excessive lipid peroxidation on cellular membranes and compromised antioxidant defenses. Multiple metabolic pathways, including iron metabolism, as well systems, contribute to the execution ferroptosis. The gut microbiota exerts regulatory effects ferroptosis through its microbial composition, biological functions, metabolites. Notably, most pathogenic bacteria tend promote ferroptosis, thereby inducing or exacerbating diseases, while probiotics have been shown protect against death. Given colonization in gut, an intimate association found between intestinal diseases microbiota. This review consolidates essential aspects ferroptotic processes, emphasizing key molecules delineating intricate interplay Moreover, this underscores potential utility modulation regulating for treatment diseases.

Язык: Английский

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Paeoniflorin confers ferroptosis resistance by regulating the gut microbiota and its metabolites in diabetic cardiomyopathy

AJP Cell Physiology, Год журнала: 2024, Номер 326(3), С. C724 - C741

Опубликована: Янв. 15, 2024

This study demonstrated for the first time that paeoniflorin (PA) exerts protective effects in diabetic cardiomyopathy mice by alleviating myocardial damage, resisting ferroptosis, and changing community composition structure of intestinal microbiota, 11,12-epoxyeicosatrienoic acid (11,12-EET) may serve as a key contributor its therapeutic efficacy.

Язык: Английский

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β‐Diketone Functionalized Microspheres Chelate Reactive Iron via Metal Coordination for Cartilage Repair

Advanced Healthcare Materials, Год журнала: 2025, Номер unknown

Опубликована: Март 5, 2025

Excessive intracellular iron accumulation can induce mitochondrial dysfunction, leading to chondrocyte ferroptosis, a key contributor cartilage damage in osteoarthritis (OA). Here, micelle-microfluidic hydrogel microspheres, featuring keto-enol-thiol bridged nano-sized secondary structures that disintegrate within the peroxidative environment reveal β-diketone groups with metal chelation capabilities, are utilized for situ removal of reactive iron, thereby facilitating repair through restoration homeostasis. The relevant experiments demonstrate microspheres reduce influx by downregulating transferrin receptor (TfR1) expression and decrease uptake upregulating outer membrane iron-sulfur cluster protein (CISD1), thus restoring Furthermore, antioxidant properties ketone-thioether segments synergistically mitigate phospholipid peroxidation via Nrf2/SLC7A11/GPX4 axis, inhibiting ferroptosis slowing OA progression. In summary, this system sustainably chelates coordination exhibits great potential minimally invasive treatment other ferroptosis-mediated diseases.

Язык: Английский

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HIF‐1α‐induced expression of the m6A reader YTHDF1 inhibits the ferroptosis of nucleus pulposus cells by promoting SLC7A11 translation

Aging Cell, Год журнала: 2024, Номер 23(9)

Опубликована: Май 23, 2024

The nucleus pulposus is in a hypoxic environment the human body, and when intervertebral disc degeneration (IVDD) occurs, disrupted. Nucleus cell (NPC) ferroptosis one of causes IVDD. N6-methyladenosine (m6A) its reader protein YTHDF1 regulate cellular activities by affecting RNA metabolism. However, regulation NPCs m6A-modified RNAs under conditions has not been as well studied. In this study, through vitro vivo experiments, we explored underlying mechanism HIF-1α regulating NPCs. results indicated that overexpression or suppressed NPC ferroptosis; conversely, knockdown increased levels Luciferase reporter assays chromatin immunoprecipitation demonstrated regulated transcription directly binding to promoter region. Polysome profiling showed promoted translation SLC7A11 consequently expression anti-ferroptosis GPX4 mRNA. conclusion, HIF-1α-induced reduces delays IVDD promoting m6A-dependent manner.

Язык: Английский

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