Protosappanin A Protects DOX‐Induced Myocardial Injury and Cardiac Dysfunction by Targeting ACSL4/FTH1 Axis‐Dependent Ferroptosis

Advanced Science, Год журнала: 2024, Номер unknown

Опубликована: Июль 10, 2024

Abstract Doxorubicin (DOX) is an effective anticancer agent, but its clinical utility constrained by dose‐dependent cardiotoxicity, partly due to cardiomyocyte ferroptosis. However, the progress of developing cardioprotective medications counteract ferroptosis has encountered obstacles. Protosappanin A (PrA), anti‐inflammatory compound derived from hematoxylin, shows potential against DOX‐induced cardiomyopathy (DIC). Here, it reported that PrA alleviates myocardial damage and dysfunction reducing maintaining mitochondrial homeostasis. Subsequently, molecular target through proteome microarray, docking, dynamics simulation identified. Mechanistically, physically binds with ferroptosis‐related proteins acyl‐CoA synthetase long‐chain family member 4 (ACSL4) ferritin heavy chain 1 (FTH1), ultimately inhibiting ACSL4 phosphorylation subsequent phospholipid peroxidation, while also preventing FTH1 autophagic degradation release ferrous ions (Fe 2+ ) release. Given critical role in pathogenesis ischemia‐reperfusion (IR) injury, this further investigation posits can confer a protective effect IR‐induced cardiac Overall, novel pharmacological inhibitor unveiled targets uncover dual‐regulated mechanism for DIC, highlighting additional therapeutic options chemodrug‐induced cardiotoxicity ferroptosis‐triggered disorders.

Язык: Английский

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Nicorandil alleviates cardiac microvascular ferroptosis in diabetic cardiomyopathy: Role of the mitochondria-localized AMPK-Parkin-ACSL4 signaling pathway

Pharmacological Research, Год журнала: 2024, Номер 200, С. 107057 - 107057

Опубликована: Янв. 11, 2024

Mitochondria-associated ferroptosis exacerbates cardiac microvascular dysfunction in diabetic cardiomyopathy (DCM). Nicorandil, an ATP-sensitive K+ channel opener, protects against endothelial dysfunction, mitochondrial and DCM; however, its effects on mitophagy remain unexplored. The present study aimed to assess the beneficial of nicorandil DCM underlying mechanisms. Cardiac perfusion was assessed using a lectin assay, while via mt-Keima transfection transmission electron microscopy. Ferroptosis examined mRNA sequencing, fluorescence staining, western blotting. localization Parkin, ACSL4, AMPK determined immunofluorescence staining. Following long-term diabetes, treatment improved function remodeling by alleviating injuries, as evidenced structural integrity. mRNA-sequencing biochemical analyses showed that occurred Pink1/Parkin-dependent suppressed cells after diabetes. Nicorandil mitochondria-associated promoting mitophagy. Moreover, increased phosphorylation level AMPKα1 promoted translocation, which further inhibited translocation ACSL4 ultimately ferroptosis. Importantly, overexpression mitochondria-localized (mitoAα1) shared similar benefits with mitophagy, cardiovascular protection injury. In conclusion, demonstrated therapeutic revealed AMPK-Parkin-ACSL4 signaling pathway mediates development dysfunction.

Язык: Английский

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Exploring the Mechanism of Ferroptosis Induction by Sappanone A in Cancer: Insights into the Mitochondrial Dysfunction Mediated by NRF2/xCT/GPX4 Axis

International Journal of Biological Sciences, Год журнала: 2024, Номер 20(13), С. 5145 - 5161

Опубликована: Янв. 1, 2024

Non-small cell lung cancer (NSCLC), a major subtype of cancer, encompasses squamous carcinoma, adenocarcinoma, and large carcinoma. Compared to small NSCLC cells grow divide more slowly, their metastasis occurs at later stage. Currently, chemotherapy is the primary treatment for this disease. Sappanone A (SA) flavonoid compound extracted from plant Caesalpinia sappan, known its antitumor, redox-regulating, anti-inflammatory properties. Recent studies have investigated interaction SA with mitochondrial pathways in regulating death through Nrf-2/GPX-4/xCT axis. This study specifically explores mechanism by which affects morphology structure regulation mitophagy biogenesis tumor cells. The primarily utilizes second-generation transcriptomic sequencing data molecular docking techniques elucidate role programmed omics results indicate that significantly targets genes involved oxidative phosphorylation, mitophagy, dynamics, stress. Further findings confirmed Nrf-2/GPX4/xCT pathway serves as crucial target NSCLC. Knockdown Nrf-2 (si-Nrf-2) overexpression (ad-Nrf-2) were shown modulate therapeutic efficacy varying degrees. Additionally, modifications GPX4/xCT affected regulatory effects on autophagy, biogenesis, energy metabolism. These mechanisms may be mediated caspase ferroptosis-related signaling. Molecular biology experiments demonstrated intervention further inhibits phosphorylation FUNDC1 Tyr18 downregulates TOM20 expression. was found reduce expression PGC1α, Nrf-1, Tfam, resulting decrease respiration Overexpression counteract biogenesis. Confocal microscopy revealed increases fragmentation, subsequently inducing pathway-mediated death. However, genetic modification altered In conclusion, has been identified promising agent apoptosis ferroptosis represent key Targeting axis offers novel approach maintaining homeostasis within cellular microenvironment.

Язык: Английский

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Sensing of mitochondrial DNA by ZBP1 promotes RIPK3-mediated necroptosis and ferroptosis in response to diquat poisoning

Cell Death and Differentiation, Год журнала: 2024, Номер 31(5), С. 635 - 650

Опубликована: Март 16, 2024

Язык: Английский

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Targeting ferroptosis: a new therapeutic opportunity for kidney diseases

Frontiers in Immunology, Год журнала: 2024, Номер 15

Опубликована: Июль 3, 2024

Ferroptosis is a form of non-apoptotic regulated cell death (RCD) that depends on iron and characterized by the accumulation lipid peroxides to lethal levels. involves multiple pathways including redox balance, regulation, mitochondrial function, amino acid, lipid, glycometabolism. Furthermore, various disease-related signaling also play role in regulating process oxidation. In recent years, with emergence concept ferroptosis in-depth study its mechanisms, closely associated biological conditions related kidney diseases, organ development, aging, immunity, cancer. This article reviews development ferroptosis, mechanisms (including GSH-GPX4, FSP1-CoQ1, DHODH-CoQ10, GCH1-BH4, MBOAT1/2 pathways), latest research progress involvement diseases. It summarizes diseases within frameworks metabolism, reactive oxygen biology, biology. The introduces key regulatory factors as well important concepts major open questions natural compounds. hoped future research, further breakthroughs can be made understanding regulation mechanism utilizing promote treatments for such acute injury(AKI), chronic disease (CKD), diabetic nephropathy(DN), renal carcinoma. paves way new approach prevent, treat clinical

Язык: Английский

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HO-1 activation contributes to cadmium-induced ferroptosis in renal tubular epithelial cells via increasing the labile iron pool and promoting mitochondrial ROS generation

Chemico-Biological Interactions, Год журнала: 2024, Номер 399, С. 111152 - 111152

Опубликована: Июль 16, 2024

Язык: Английский

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Hippo pathway activation mediates cardiomyocyte ferroptosis to promote dilated cardiomyopathy through downregulating NFS1

Redox Biology, Год журнала: 2025, Номер unknown, С. 103597 - 103597

Опубликована: Март 1, 2025

Язык: Английский

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Iron toxicity, ferroptosis and microbiota in Parkinson’s disease: Implications for novel targets

Advances in neurotoxicology, Год журнала: 2024, Номер unknown, С. 105 - 132

Опубликована: Янв. 1, 2024

Язык: Английский

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Deciphering the link: ferroptosis and its role in glioma

Frontiers in Immunology, Год журнала: 2024, Номер 15

Опубликована: Янв. 23, 2024

Glioma, as the most frequently occurring primary malignancy in central nervous system, significantly impacts patients' quality of life and cognitive abilities. Ferroptosis, a newly discovered form cell death, is characterized by significant iron accumulation lipid peroxidation. This process fundamentally dependent on iron. Various factors inducing ferroptosis can either directly or indirectly influence glutathione peroxidase, leading to reduced antioxidant capabilities an increase reactive oxygen species (ROS) within cells, culminating oxidative death. Recent research indicates strong connection between range pathophysiological conditions, including tumors, neurological disorders, ischemia-reperfusion injuries, kidney damage, hematological diseases. The regulation intervene progression these diseases has emerged major area interest etiological therapy. However, exact functional alterations molecular mechanisms underlying remain be extensively studied. review firstly explores intricate relationship glioma, highlighting how contributes glioma pathogenesis cells may resist this Then, we discuss recent studies that have identified potential inducers inhibitors, which could serve novel therapeutic strategies for glioma. We also examine current challenges targeting treatment, complexity its need precise delivery methods. aims provide comprehensive overview state offering insights into future broader implications death pathway cancer biology.

Язык: Английский

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Metaplastic regeneration in the mouse stomach requires a reactive oxygen species pathway

Developmental Cell, Год журнала: 2024, Номер 59(9), С. 1175 - 1191.e7

Опубликована: Март 22, 2024

Язык: Английский

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