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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Renal tubular epithelial cells response to injury in acute kidney injury

EBioMedicine, Journal Year: 2024, Volume and Issue: 107, P. 105294 - 105294

Published: Aug. 23, 2024

Acute kidney injury (AKI) is a clinical syndrome characterized by rapid and significant decrease in renal function that can arise from various etiologies, associated with high morbidity mortality. The tubular epithelial cells (TECs) represent the central cell type affected AKI, their notable regenerative capacity critical for recovery of afflicted patients. adaptive repair process initiated surviving TECs following mild AKI facilitates full recovery. Conversely, when severe or persistent, it allows to undergo pathological responses, abnormal phenotypic transformation, which will lead development fibrosis. Given implications fate after outcomes, deeper understanding these mechanisms necessary identify promising therapeutic targets biomarkers human kidney.

Language: Английский

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Human proximal tubular epithelial cell-derived small extracellular vesicles mediate synchronized tubular ferroptosis in hypoxic kidney injury

Redox Biology, Journal Year: 2024, Volume and Issue: 70, P. 103042 - 103042

Published: Jan. 15, 2024

Hypoxia is the key pathobiological trigger of tubular oxidative stress and cell death that drives transition acute kidney injury (AKI) to chronic disease (CKD). The mitochondrial-rich proximal epithelial cells (PTEC) are uniquely sensitive hypoxia thus, pivotal in propagating sustained loss AKI-to-CKD transition. Here, we examined role PTEC-derived small extracellular vesicles (sEV) 'wave death'. Ex vivo patient-derived PTEC were cultured under normoxia (21 % O2) (1 on Transwell inserts for isolation analysis sEV secreted from apical versus basolateral surfaces. Increased numbers surface hypoxic compared with normoxic PTEC. No differences observed between culture conditions. Biological pathway hypoxic-apical cargo identified distinct miRNAs linked cellular pathways. In functional assays, selectively induced ferroptotic (↓glutathione peroxidase-4, ↑lipid peroxidation) autologous normoxic-apical sEV. addition ferroptosis inhibitors, ferrostatin-1 baicalein, attenuated ferroptosis. RNAse A pretreatment also abrogated ferroptosis, demonstrating a RNA death' signalling. line these vitro findings, situ immunolabelling diagnostic biopsies AKI patients clinical progression CKD (AKI-to-CKD transition) showed evidence propagation (increased ACSL4+ PTEC), while urine-derived (usEV) 'AKI-to-CKD transition' triggered (↑lipid studies. Our data establish their intravesicular as mediators lipid peroxidation injury. This concept how pathology propagated initiating insult into provides novel therapeutic check-points targeting

Language: Английский

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METTL3 mediates CPB1 expression by regulating transcription factor BACH2 to promote apoptosis and oxidative stress of lens epithelial cells

Journal of Bioenergetics and Biomembranes, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 21, 2025

Language: Английский

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Ultrasmall platinum single-atom enzyme alleviates oxidative stress and macrophage polarization induced by acute kidney ischemia–reperfusion injury through inhibition of cell death storm

Journal of Nanobiotechnology, Journal Year: 2025, Volume and Issue: 23(1)

Published: April 27, 2025

Acute kidney injury (AKI), characterized by a rapid decline in renal function, is associated with impaired mitochondrial function and excessive reactive oxygen species (ROS). Therefore, the exploration of ROS scavengers provides promising new opportunities for prevention treatment AKI mitigating oxidative stress. Here, we construct an ultrasmall platinum single-atom enzyme (Pt/SAE) multiple antioxidant activities to protect against acute ischemia-reperfusion (I/R) injury. Pt/SAE not only mimics superoxide dismutase catalase convert anion into water oxygen, but also exhibits impressive hydroxyl radical scavenging capacity, thereby reducing pro-inflammatory macrophage levels preventing inflammation. Furthermore, reduces accumulation Z-form DNA, which excessively accumulates following I/R damage, thus decreasing its interaction Z-DNA binding protein 1, consequently progression PANoptosis Additionally, downregulation induced suppresses lipid peroxidation, return ferroptosis I/R. Both vitro vivo experiments confirm that effectively mitigates inflammatory cell infiltration promotes shift polarization from M1-like M2-like subtype. This study information development novel SAEs as viable method AKI.

Language: Английский

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Micro electrical fields induced MSC-sEVs attenuate neuronal cell apoptosis by activating autophagy via lncRNA MALAT1/miR-22-3p/SIRT1/AMPK axis in spinal cord injury

Journal of Nanobiotechnology, Journal Year: 2023, Volume and Issue: 21(1)

Published: Nov. 27, 2023

Language: Английский

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NAT10 promotes renal ischemia-reperfusion injury via activating NCOA4-mediated ferroptosis

Heliyon, Journal Year: 2024, Volume and Issue: 10(2), P. e24573 - e24573

Published: Jan. 1, 2024

Ischemia-reperfusion injury (IRI) is a significant contributor to acute kidney (AKI) and associated with substantial morbidity mortality rates. In this study, we aimed investigate the role of NAT10 its ac4C RNA modification in IRI-induced renal injury. Our findings revealed that both expression level kidneys were elevated IRI group compared sham group. Functionally, observed inhibition activity Remodelin or specific knockout led attenuation Furthermore, vitro experiments demonstrated markedly suppressed global modification, providing protection against hypoxia/reoxygenation-induced tubular epithelial cell ferroptosis. Mechanistically, our study uncovered promoted NCOA4 mRNA, thereby enhancing stability contributing ferroptosis cells (TECs). These underscore potential as promising therapeutic targets for treatment AKI. Overall, sheds light on critical involvement pathogenesis injury, offering valuable insights development novel AKI strategies.

Language: Английский

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Ferroptosis-related exosomal non-coding RNAs: promising targets in pathogenesis and treatment of non-malignant diseases

Frontiers in Cell and Developmental Biology, Journal Year: 2024, Volume and Issue: 12

Published: Feb. 7, 2024

Ferroptosis, an iron-dependent form of programmed cell death, introduces a novel perspective on cellular demise. This study investigates the regulatory network exosomal non-coding RNAs (ncRNAs), including miRNAs, circRNAs, and lncRNAs, in ferroptosis modulation. The primary goal is to examine pathological roles ferroptosis-related ncRNAs, particularly ischemic reperfusion injuries. research reveals intricate molecular interactions governing interplay between ncRNAs ferroptosis, elucidating their diverse different non-malignant contexts. Attention given impact diseases, cardiac, cerebral, liver, kidney injuries, as well lung, wound, neuronal Beyond theoretical exploration, provides insights into potential therapeutic applications, emphasizing significance mesenchymal stem cells (MSCs)-derived exosomes. Findings underscore pivotal role MSC-derived modulating responses related regulation, introducing cutting-edge dimension. recognition emphasizes importance exosomes crucial mediators with broad implications. Insights unveil promising avenues for targeted interventions, capitalizing providing comprehensive foundation future strategies.

Language: Английский

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Extracellular vesicles secreted from mesenchymal stem cells ameliorate renal ischemia reperfusion injury by delivering miR-100-5p targeting FKBP5/AKT axis

Scientific Reports, Journal Year: 2024, Volume and Issue: 14(1)

Published: March 20, 2024

Abstract The incidence of acute kidney injury (AKI) due to ischemia–reperfusion (IR) is increasing. There no effective treatment for AKI, and because this clinical challenge, AKI often progresses chronic disease, which closely associated with poor patient outcomes high mortality rates. Small extracellular vesicles from human umbilical cord mesenchymal stem cells (hUCMSC-sEVs) play increasingly vital roles in protecting tissue function the effects various harmful stimuli owing their specific biological features. In study, we found that miR-100-5p was enriched hUCMSC-sEVs, targeted FKBP5 inhibited HK-2 cell apoptosis by activating AKT pathway. were exposed IR cocultured leading an increase levels, a decrease phosphorylation at Ser 473 (AKT-473 phosphorylation). Notably, these significantly reversed transfecting hUCMSCs inhibitor. Moreover, FKBP5, as confirmed dual luciferase reporter assay. vivo, intravenous infusion hUCMSC-sEVs into mice suffering resulted significant inhibition, functional maintenance renal histological protection, turn decreased expression levels. Overall, study revealed effect on inhibiting apoptosis; reduced delivering cells, targeting thereby promoting AKT-473 activate This provides novel insights role AKI.

Language: Английский

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Ferroptosis regulation by Cap’n’collar family transcription factors

Journal of Biological Chemistry, Journal Year: 2024, Volume and Issue: 300(8), P. 107583 - 107583

Published: July 16, 2024

Ferroptosis is an iron-dependent cell death mechanism that may be important to prevent tumor formation and useful as a target for new cancer therapies. Transcriptional networks play crucial role in shaping ferroptosis sensitivity by regulating the expression of transporters, metabolic enzymes, other proteins. The Cap'n'collar (CNC) protein nuclear factor erythroid 2 like (NFE2L2, also known NRF2) key regulator many cells contexts. Emerging evidence indicates related CNC family members BTB homology 1 (BACH1) (NFE2L1) have non-redundant roles regulation. Here, we comprehensively review transcription factors governing cellular ferroptosis. We describe how regulate through modulation iron, lipid, redox metabolism. use examples regulation proteins illustrate flexible highly context-dependent nature between conditions.

Language: Английский

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