Ferroptosis turns 10: Emerging mechanisms, physiological functions, and therapeutic applications

Cell, Journal Year: 2022, Volume and Issue: 185(14), P. 2401 - 2421

Published: July 1, 2022

Ferroptosis, a form of cell death driven by iron-dependent lipid peroxidation, was identified as distinct phenomenon and named decade ago. Ferroptosis has been implicated in broad set biological contexts, from development to aging, immunity, cancer. This review describes key regulators this within framework metabolism, ROS biology, iron biology. Key concepts major unanswered questions the ferroptosis field are highlighted. The next promises yield further breakthroughs mechanisms governing additional ways harnessing for therapeutic benefit.

Language: Английский

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Kidney fibrosis: from mechanisms to therapeutic medicines

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

Published: March 17, 2023

Abstract Chronic kidney disease (CKD) is estimated to affect 10–14% of global population. Kidney fibrosis, characterized by excessive extracellular matrix deposition leading scarring, a hallmark manifestation in different progressive CKD; However, at present no antifibrotic therapies against CKD exist. fibrosis identified tubule atrophy, interstitial chronic inflammation and fibrogenesis, glomerulosclerosis, vascular rarefaction. Fibrotic niche, where organ initiates, complex interplay between injured parenchyma (like tubular cells) multiple non-parenchymal cell lineages (immune mesenchymal located spatially within scarring areas. Although the mechanisms are complicated due kinds cells involved, with help single-cell technology, many key questions have been explored, such as what kind renal tubules profibrotic, myofibroblasts originate, which immune how communicate each other. In addition, genetics epigenetics deeper that regulate fibrosis. And reversible nature epigenetic changes including DNA methylation, RNA interference, chromatin remodeling, gives an opportunity stop or reverse therapeutic strategies. More marketed (e.g., RAS blockage, SGLT2 inhibitors) developed delay progression recent years. Furthermore, better understanding also favored discover biomarkers fibrotic injury. review, we update advances mechanism summarize novel treatment for CKD.

Language: Английский

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Ferroptotic mechanisms and therapeutic targeting of iron metabolism and lipid peroxidation in the kidney

Nature Reviews Nephrology, Journal Year: 2023, Volume and Issue: 19(5), P. 315 - 336

Published: March 15, 2023

Language: Английский

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Mechanisms and Models of Kidney Tubular Necrosis and Nephron Loss

Journal of the American Society of Nephrology, Journal Year: 2022, Volume and Issue: 33(3), P. 472 - 486

Published: Jan. 12, 2022

Understanding nephron loss is a primary strategy for preventing CKD progression. Death of renal tubular cells may occur by apoptosis during developmental and regenerative processes. However, AKI, the transition AKI to CKD, sepsis-associated kidney transplantation ferroptosis necroptosis, two pathways associated with plasma membrane integrity, kill cells. This necrotic type cell death an inflammatory response, which referred as necroinflammation. Importantly, necroinflammatory response that die necroptosis be fundamentally different from tissue ferroptosis. Although mechanisms have recently been investigated in detail, propagation necrosis, although described morphologically, remains incompletely understood. Here, we argue molecular switch downstream necrosis determines regeneration versus loss. Unraveling details this "switch" must include signals potentially controlled cells, including stimulation myofibroblasts origin fibrosis. detail responses can inform discussion therapeutic options.

Language: Английский

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Single-cell analysis highlights differences in druggable pathways underlying adaptive or fibrotic kidney regeneration

Nature Communications, Journal Year: 2022, Volume and Issue: 13(1)

Published: July 11, 2022

The kidney has tremendous capacity to repair after acute injury, however, pathways guiding adaptive and fibrotic are poorly understood. We developed a model of regeneration by titrating ischemic injury dose. performed detailed biochemical histological analysis profiled transcriptomic changes at bulk single-cell level (> 110,000 cells) over time. Our highlights proximal tubule cells as key susceptible injury. Adaptive correlated with fatty acid oxidation oxidative phosphorylation. identify specific maladaptive/profibrotic cluster long ischemia, which expresses proinflammatory profibrotic cytokines myeloid cell chemotactic factors. Druggability pyroptosis/ferroptosis vulnerable in these cells. Pharmacological targeting vivo pushed towards ameliorates fibrosis. In summary, our defines differences identifies druggable for pharmacological intervention prevent

Language: Английский

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Polyunsaturated Fatty Acids Drive Lipid Peroxidation during Ferroptosis

Cells, Journal Year: 2023, Volume and Issue: 12(5), P. 804 - 804

Published: March 4, 2023

Ferroptosis is a form of regulated cell death that intricately linked to cellular metabolism. In the forefront research on ferroptosis, peroxidation polyunsaturated fatty acids has emerged as key driver oxidative damage membranes leading death. Here, we review involvement (PUFAs), monounsaturated (MUFAs), lipid remodeling enzymes and in highlighting studies revealing how using multicellular model organism Caenorhabditis elegans contributes understanding roles specific lipids mediators ferroptosis.

Language: Английский

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Lineage Tracing and Single-Nucleus Multiomics Reveal Novel Features of Adaptive and Maladaptive Repair after Acute Kidney Injury

Journal of the American Society of Nephrology, Journal Year: 2023, Volume and Issue: 34(4), P. 554 - 571

Published: Jan. 13, 2023

Significance Statement Understanding the mechanisms underlying adaptive and maladaptive renal repair after AKI their long-term consequences is critical to kidney health. The authors used lineage tracing of cycling cells single-nucleus multiomics (profiling transcriptome chromatin accessibility) AKI. They demonstrated that triggers a cell-cycle response in most epithelial nonepithelial cell types. also showed proinflammatory proximal tubule (PTCs) persist until 6 months post-AKI, although they decreased abundance over time, part, through death. Single-nucleus lineage-traced revealed regulatory features repair. These included activation state–specific transcription factors cis-regulatory elements, effects PTCs even repair, weeks injury event. Background proliferative as part an intrinsic cellular program, which can lead restoring structure function, or with persistence injured altered structure. However, molecular understanding these programs limited. Methods To examine transcriptional responses same upon ischemia-reperfusion (IRI), we combined genetic fate mapping ( Ki67 + ) labeled early IRI multiomics—profiling accessibility nucleus—and generated dataset 83,315 nuclei. Results triggered broad cycle preceded by type–specific global changes nephron, collecting vascular systems, stromal immune We observed heterogeneous population throughout segments marked loss from 4 months. Gene expression profiling nuclei highlighted differences between activity elements factors, accompanied corresponding target gene expression. Adaptive was associated reduced genes encoding transmembrane transport proteins essential function. Conclusions Analysis genome organization single-cell resolution using offers new insight into regulation Weeks mild-to-moderate IRI, aberrant epigenetic landscape, exhibit profile following

Language: Английский

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STING/ACSL4 axis-dependent ferroptosis and inflammation promote hypertension-associated chronic kidney disease

Molecular Therapy, Journal Year: 2023, Volume and Issue: 31(10), P. 3084 - 3103

Published: Aug. 2, 2023

Hypertension is a primary modifiable risk factor for cardiovascular diseases, which often induces renal end-organ damage and complicates chronic kidney disease (CKD). In the present study, histological analysis of human samples revealed that hypertension induced mtDNA leakage promoted expression stimulator interferon genes (STING) in epithelial cells. We used angiotensin II (AngII)- 2K1C-treated mouse kidneys to elucidate underlying mechanisms. Abnormal packing caused by AngII STING-dependent production inflammatory cytokines, macrophage infiltration, fibrogenic response. STING knockout significantly decreased nuclear factor-κB activation immune cell attenuating tubule atrophy extracellular matrix accumulation vivo vitro. These effects delayed CKD progression. Immunoprecipitation assays liquid chromatography-tandem mass spectrometry showed ACSL4 were directly combined at D53 K412 amino acids ACSL4. Furthermore, response fibrosis through ACSL4-dependent ferroptosis. Last, inhibition using small interfering RNA, rosiglitazone, or Fer-1 downregulated AngII-induced mtDNA-STING-dependent inflammation. results suggest targeting STING/ACSL4 axis might represent potential strategy treating hypertension-associated CKD.

Language: Английский

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The Road from AKI to CKD: Molecular Mechanisms and Therapeutic Targets of Ferroptosis

Cell Death and Disease, Journal Year: 2023, Volume and Issue: 14(7)

Published: July 13, 2023

Abstract Acute kidney injury (AKI) is a prevalent pathological condition that characterized by precipitous decline in renal function. In recent years, growing body of studies have demonstrated maladaptation following AKI results chronic disease (CKD). Therefore, targeting the transition to CKD displays excellent therapeutic potential. However, mechanism mediated multifactor, and there still lack effective treatments. Ferroptosis, novel nonapoptotic form cell death, believed role progression. this study, we retrospectively examined history characteristics ferroptosis, summarized ferroptosis’s research progress CKD, discussed how ferroptosis participates regulating progression CKD. Furthermore, highlighted limitations present projected future evolution ferroptosis. We hope work will provide clues for further contribute study targets prevent diseases.

Language: Английский

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Epithelial–mesenchymal transition in tissue repair and degeneration

Nature Reviews Molecular Cell Biology, Journal Year: 2024, Volume and Issue: 25(9), P. 720 - 739

Published: April 29, 2024

Language: Английский

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