Ferroptosis inhibitors: past, present and future

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

Published: May 23, 2024

Ferroptosis is a non-apoptotic mode of programmed cell death characterized by iron dependence and lipid peroxidation. Since the ferroptosis was proposed, researchers have revealed mechanisms its formation continue to explore effective inhibitors in disease. Recent studies shown correlation between pathological neurodegenerative diseases, as well diseases involving tissue or organ damage. Acting on ferroptosis-related targets may provide new strategies for treatment ferroptosis-mediated diseases. This article specifically describes metabolic pathways summarizes reported action natural synthetic small molecule their efficacy The paper also treatments such gene therapy, nanotechnology, summarises challenges encountered clinical translation inhibitors. Finally, relationship other modes discussed, hopefully paving way future drug design discovery.

Language: Английский

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Targeting the regulation of iron homeostasis as a potential therapeutic strategy for nonalcoholic fatty liver disease

Metabolism, Journal Year: 2024, Volume and Issue: 157, P. 155953 - 155953

Published: June 15, 2024

Language: Английский

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Cordycepin alleviates metabolic dysfunction-associated liver disease by restoring mitochondrial homeostasis and reducing oxidative stress via Parkin-mediated mitophagy

Biochemical Pharmacology, Journal Year: 2025, Volume and Issue: 232, P. 116750 - 116750

Published: Jan. 8, 2025

The prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) keeps rising with only a few drugs available. present study aims to investigate the effects and mechanisms cordycepin on MASLD. Male C57BL/6 mice were induced 90-day high-fat diet (HFD) intraperitoneal administration streptozotocin establish MASLD murine model. Then they randomly divided into HFD groups (15, 30, 45 mg/kg). Cordycepin was orally given for 30 days. Serum total cholesterol (TC), triacylglyceride (TG), aspartate aminotransferase (AST) levels measured. L02 cells by oleate acid (OA) or lipopolysaccharides (LPS), treated combined inhibitors including chloroquine, 3-Methyladenine, compound C. Atg7 Parkin knocked down in using siRNA. Oil Red O Nile staining measuring lipid deposition. Mitochondria visualized transfection mCherry-TOMM20-N10. Quantitative real-time PCR, Western blotting, immunofluorescence used determine expressions key molecules inflammation, metabolism, mitochondria homeostasis, oxidative stress. significantly mitigated deposition ballooning livers mice. TC, TG, AST decreased cordycepin. alleviated OA-induced LPS-induced inflammation cells, attenuated stress, promoted autophagy, maintained autophagic flux activating AMP-activated protein kinase (AMPK). reduced accumulation impaired enhancing Parkin-dependent mitophagy promoting mitochondrial biogenesis. alleviates restoring homeostasis reducing stress via Parkin-mediated mitophagy.

Language: Английский

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Puerarin Ameliorates the Ferroptosis in Diabetic Liver Injure Through the JAK2/STAT3 Pathway Inhibition Based on Network Pharmacology and Experimental Validation

Drug Design Development and Therapy, Journal Year: 2025, Volume and Issue: Volume 19, P. 737 - 757

Published: Feb. 1, 2025

Background: Diabetic liver injury (DLI) is a common complication of diabetes mellitus (DM), which seriously endangers the health diabetic patients. Puerarin, main active component Pueraria lobata , has shown positive effects in lowering blood glucose and lipids, resisting oxidative stress, protecting liver. However, mechanism protective effect Puerarin on DLI remains unclear. Methods: Various databases were used to screen for targets ferroptosis DLI. Protein-protein interaction (PPI) network Kyoto Encyclopedia Genes Genomes (KEGG) enrichment analysis predict key pathways. Molecular docking was interactions between core targets. KK/Upj-Ay/J (KKAy) mice high (HG)-induced AML12 cells study The molecular mechanisms by acts further verified vivo vitro experiments. Results: KEGG indicated that JAK/STAT pathway might be related anti-DLI Puerarin. revealed good affinity JAK2 STAT3. In vivo, (80 mg/kg) reduced body weight, glucose, lipids function KKAy fed high-sugar, high-fat diet. also ameliorated hepatic pathological changes inflammatory responses, attenuated stress iron overload mice. Western blotting results showed could regulate expression proteins JAK2/STAT3 pathway. vitro, (25, 50, 100 μM) increased cell viability decreased steatosis indexes induced HG (30 mm) varying degrees. More importantly, AG490 blocker experiments regulation process dependent Conclusion: conclusion, this may inhibiting treatment Keywords: puerarin, injury, ferroptosis, pathway, pharmacology

Language: Английский

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The emerging role of E3 ubiquitin ligases and deubiquitinases in metabolic dysfunction-associated steatotic liver disease

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

Published: March 25, 2025

Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common chronic worldwide, with a prevalence as high 32.4%. MASLD encompasses spectrum of pathologies, ranging from steatosis to metabolic steatohepatitis (MASH), fibrosis, and, in some cases, progression end-stage (cirrhosis and hepatocellular carcinoma). A comprehensive understanding pathogenesis this highly prevalent may facilitate identification novel targets for development improved therapies. E3 ubiquitin ligases deubiquitinases (DUBs) are key regulatory components ubiquitin‒proteasome system (UPS), which plays pivotal role maintaining intracellular protein homeostasis. Emerging evidence implicates that aberrant expression DUBs involved MASLD. Here, we review abnormalities by (1) discussing their targets, mechanisms, functions MASLD; (2) summarizing pharmacological interventions targeting these enzymes preclinical clinical studies; (3) addressing challenges future therapeutic strategies. This synthesizes current highlight strategies based on UPS progressive disease.

Language: Английский

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Examining the Pathogenesis of MAFLD and the Medicinal Properties of Natural Products from a Metabolic Perspective

Metabolites, Journal Year: 2024, Volume and Issue: 14(4), P. 218 - 218

Published: April 12, 2024

Metabolic-associated fatty liver disease (MAFLD), characterized primarily by hepatic steatosis, has become the most prevalent worldwide, affecting approximately two-fifths of global population. The pathogenesis MAFLD is extremely complex, and to date, there are no approved therapeutic drugs for clinical use. Considerable evidence indicates that various metabolic disorders play a pivotal role in progression MAFLD, including lipids, carbohydrates, amino acids, micronutrients. In recent years, medicinal properties natural products have attracted widespread attention, numerous studies reported their efficacy ameliorating subsequently alleviating MAFLD. This review aims summarize metabolic-associated pathological mechanisms as well regulate pathways alleviate

Language: Английский

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Unveiling the role of ferroptosis in the progression from NAFLD to NASH: recent advances in mechanistic understanding

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

Published: July 4, 2024

Non-alcoholic fatty liver disease (NAFLD) is a prevalent and significant global public health issue. Nonalcoholic steatohepatitis (NASH) represents an advanced stage of NAFLD in terms pathology. However, the intricate mechanisms underlying progression from to NASH remain elusive. Ferroptosis, characterized by iron-dependent cell death distinguished other forms based on morphological, biochemical, genetic criteria, has emerged as potential participant with pivotal role driving progression. Nevertheless, its precise mechanism remains poorly elucidated. In this review article, we comprehensively summarize pathogenesis NAFLD/NASH ferroptosis while highlighting recent advances understanding mechanistic involvement NAFLD/NASH.

Language: Английский

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Targeting cell death in NAFLD: mechanisms and targeted therapies

Cell Death Discovery, Journal Year: 2024, Volume and Issue: 10(1)

Published: Sept. 7, 2024

Language: Английский

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Cellular preconditioning and mesenchymal stem cell ferroptosis

World Journal of Stem Cells, Journal Year: 2024, Volume and Issue: 16(2), P. 64 - 69

Published: Feb. 25, 2024

In this editorial, we comment on the article published in recent issue of

Language: Английский

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Ferroptosis at the nexus of metabolism and metabolic diseases

Theranostics, Journal Year: 2024, Volume and Issue: 14(15), P. 5826 - 5852

Published: Jan. 1, 2024

Ferroptosis, an iron-dependent form of regulated cell death, is emerging as a crucial regulator human physiology and pathology. Increasing evidence showcases reciprocal relationship between ferroptosis dysregulated metabolism, propagating pathogenic vicious cycle that exacerbates pathology diseases, particularly metabolic disorders. Consequently, there rapidly growing interest in developing ferroptosis-based therapeutics. Therefore, comprehensive understanding the intricate interplay metabolism could provide invaluable resource for mechanistic insight therapeutic development. In this review, we summarize important substances associated pathways initiation progression, outline cascade responses disease development, overview roles mechanisms introduce methods detection, discuss perspectives ferroptosis, which collectively aim to illustrate view basic, translational, clinical science.

Language: Английский

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