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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cAMP-PKA/EPAC signaling and cancer: the interplay in tumor microenvironment

Journal of Hematology & Oncology, Journal Year: 2024, Volume and Issue: 17(1)

Published: Jan. 17, 2024

Cancer is a complex disease resulting from abnormal cell growth that induced by number of genetic and environmental factors. The tumor microenvironment (TME), which involves extracellular matrix, cancer-associated fibroblasts (CAF), tumor-infiltrating immune cells angiogenesis, plays critical role in progression. Cyclic adenosine monophosphate (cAMP) second messenger has pleiotropic effects on the TME. downstream effectors cAMP include cAMP-dependent protein kinase (PKA), exchange activated (EPAC) ion channels. While can activate PKA or EPAC promote cancer growth, it also inhibit proliferation survival context- type-dependent manner. Tumor-associated stromal cells, such as CAF release cytokines factors either stimulate production within Recent studies have shown targeting signaling TME therapeutic benefits cancer. Small-molecule agents adenylate cyclase been to growth. In addition, cAMP-elevating agents, forskolin, not only induce death, but directly some types. this review, we summarize current understanding biology immunology discuss basis for its context-dependent dual oncogenesis. Understanding precise mechanisms interact will be development effective therapies. Future aimed at investigating cAMP-cancer axis regulation may provide new insights into underlying tumorigenesis lead novel strategies.

Language: Английский

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Melatonin MT1 receptors regulate the Sirt1/Nrf2/Ho‐1/Gpx4 pathway to prevent α‐synuclein‐induced ferroptosis in Parkinson's disease

Journal of Pineal Research, Journal Year: 2024, Volume and Issue: 76(2)

Published: March 1, 2024

Abstract Parkinson's disease (PD) is a neurodegenerative disorder characterized by the loss of dopaminergic (DA) neurons and aggregation α‐synuclein (α‐syn). Ferroptosis, form cell death induced iron accumulation lipid peroxidation, involved in pathogenesis PD. It unknown whether melatonin receptor 1 (MT1) modulates α‐syn ferroptosis Here, we used preformed fibrils (PFFs) to induce PD models vivo vitro. In mice, led increased deposition ferroptosis. MT1 knockout exacerbated these changes resulted more DA neuronal severe motor impairment. also suppressed Sirt1/Nrf2/Ho1/Gpx4 pathway, reducing resistance ferroptosis, inhibited expression ferritin Fth1, leading release ferrous ions. vitro experiments confirmed findings. Knockdown enhanced PFF‐induced intracellular pathway Fth1 protein, thereby aggravating Conversely, overexpression reversed effects. Our findings reveal novel mechanism which activation prevents α‐syn‐induced PD, highlighting neuroprotective role

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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Ferroptosis: Biology and Role in Gastrointestinal Disease

Gastroenterology, Journal Year: 2024, Volume and Issue: 167(2), P. 231 - 249

Published: March 1, 2024

Language: Английский

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The potential influence of melatonin on mitochondrial quality control: a review

Frontiers in Pharmacology, Journal Year: 2024, Volume and Issue: 14

Published: Jan. 11, 2024

Mitochondria are critical for cellular energetic metabolism, intracellular signaling orchestration and programmed death regulation. Therefore, mitochondrial dysfunction is associated with various pathogeneses. The maintenance of homeostasis functional recovery after injury coordinated by biogenesis, dynamics autophagy, which collectively referred to as quality control. There increasing evidence that mitochondria important targets melatonin exert protective effects under pathological conditions. Melatonin, an evolutionarily conserved tryptophan metabolite, can be synthesized, transported metabolized in mitochondria. In this review, we summarize the role damaged elimination energy supply regulating control, may provide new strategies clinical treatment mitochondria-related diseases.

Language: Английский

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Exogenous hydrogen sulfide improves non-alcoholic fatty liver disease by inhibiting endoplasmic reticulum stress/NLRP3 inflammasome pathway

Molecular and Cellular Biochemistry, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 8, 2025

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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Melatonin and ferroptosis: Mechanisms and therapeutic implications

Biochemical Pharmacology, Journal Year: 2023, Volume and Issue: 218, P. 115909 - 115909

Published: Nov. 4, 2023

Language: Английский

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Dyslipidemia-induced renal fibrosis related to ferroptosis and endoplasmic reticulum stress

Journal of Lipid Research, Journal Year: 2024, Volume and Issue: 65(9), P. 100610 - 100610

Published: July 31, 2024

Dyslipidemia may induce chronic kidney disease and trigger both ferroptosis endoplasmic reticulum (ER) stress, but the instigating factors are incompletely understood. We tested hypothesis that different models of dyslipidemia engage distinct injury mechanisms. Wild-type (WT) or proprotein-convertase subtilisin/kexin type-9 (PCSK9)-gain-of-function (GOF) Ossabaw pigs were fed with a 6-month normal diet (ND) high-fat (HFD) (n = 5-6 each). Renal function fat deposition studied in vivo using CT, blood tissue ex-vivo for lipid profile, systemic renal vein FFAs levels, mechanisms including peroxidation, ferroptosis, ER stress. Compared WT-ND pigs, HFD PCSK9-GOF elevated triglyceride which highest WT-HFD, whereas total LDL cholesterol levels rose only particularly PCSK9-GOF/HFD. The groups had worse than ND groups. WT-HFD kidneys retained more FFA other groups, all developed fibrosis. Furthermore, HFD-induced indicated by increased free iron, decreased glutathione peroxidase-4 mRNA expression, while induced stress upregulated GRP94 CHOP protein expression. In vitro, pig epithelial cells treated palmitic acid oxidized to mimic showed similar trends those observed vivo. Taken together, hypertriglyceridemia promotes retention PCSK9-GOF-induced hypercholesterolemia elicits resulting These observations suggest targets preventing treating fibrosis subjects specific types dyslipidemia.

Language: Английский

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