CHEMICAL ENGINEERING JOURNAL
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2024
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IF 13.3
Kai Zhang,Xueyan Mao,Houming Zhao,Alberto Bianco,Shaohua Ge,Baojin Ma
Ferroptosis has been identified as a prevalent pathological process in both infectious and non-infectious inflammation. Multiregional iron accumulation within extracellular, cytoplasmic, and subcellular compartments, particularly into mitochondria, can trigger lipid peroxidation and subsequent ferroptosis. Meanwhile, mitochondrial dysfunction, as a hallmark feature of ferroptosis, also exacerbates ferroptosis and inflammation. Here, a strategy of multi-hierarchy iron chelation coupled with mitochondrial homeostasis regulation is proposed to inhibit ferroptosis and relieve inflammation based on selenium-doped carbon dots (SeCDs). SeCDs with reactive oxygen species (ROS) scavenging capacity can be efficiently internalized into cells and enriched in mitochondria. Through the multi-hierarchy chelation for extracellular, cytoplasmic, and mitochondrial iron, iron overload is remarkably inhibited. Meanwhile, promoting glutathione peroxidase 4 (GPX4) expression and activating the AMPK pathway can restrain the metabolism of glycerophospholipids and polyunsaturated fatty acids and lipid peroxidation. Importantly, SeCDs restore mitochondrial homeostasis by chelating mitochondrial iron, scavenging mtROS, and increasing the level of GPX4, thereby enhancing ferroptosis suppression. Further, SeCDs rescue the osteogenic differentiation potential of stem cells, which is generally weakened by ferroptosis. In vivo experiments prove that SeCDs can significantly inhibit ferroptosis and inflammation, and facilitate tissue regeneration. Thus, this multifunctional nanosystem provides a promising therapeutic strategy to inhibit ferroptosis and ease inflammation.
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高影响因子
JOURNAL OF ENVIRONMENTAL MANAGEMENT
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2025
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IF 8.4
Xiaotian Huang,Zuhong Lin,Denglong Lu,Haipu Li
Tetrabromobisphenol A (TBBPA), a brominated flame retardant extensively used in consumer electronics, has been classified as a persistent environmental contaminant. While TBBPA-induced mitochondrial dysfunction is implicated in apoptosis, the precise oxidative stress-mediated mechanisms remain incompletely characterized. In this study, using human liver cancer cells (HepG 2 ) as an in vitro model, we systematically investigated TBBPA's mitochondrial toxicity and associated cell death pathways. In vitro assays demonstrated that 10 μM TBBPA induced approximately 50 % cell death and reduced cell viability. This treatment also markedly elevated intracellular reactive oxygen species (ROS) levels. A comprehensive analysis of mitochondrial function, including assessments of mitochondrial membrane potential (MMP), oxygen consumption rate (OCR), ATP production, respiratory chain complex activities, and mitochondrial autophagy markers (LC3B, PINK1, Parkin), revealed that TBBPA entry into cells resulted in mitochondrial dysfunction. Furthermore, Ferroptosis biomarkers quantification further revealed TBBPA-driven Fe 2+ and malondialdehyde (MDA) accumulation, coupled with upregulated expression of ferroptosis-related proteins (GPX4, SLC7A11, COX-2, Beclin-1). These findings provide novel insights into the molecular pathways underlying TBBPA-induced cytotoxicity.
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高影响因子
MOLECULAR MEDICINE
·
2024
·Vol. 30
·期 1
·1-14
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IF 6
Yu Hao,Gan Daojing,Luo Zhen,Yang Qilin,An Dongqi,Zhang Hao,Hu Yingchun,Ma Zhuang,Zeng Qingchun,Xu Dingli,Ren Hao
Background In heart failure (HF), mitochondrial dysfunction and metabolic remodeling lead to a reduction in energy productivity and aggravate cardiomyocyte injury. Supplementation with α-ketoglutarate (AKG) alleviated myocardial hypertrophy and fibrosis in mice with HF and improved cardiac insufficiency. However, the myocardial protective mechanism of AKG remains unclear. We verified the hypothesis that AKG improves mitochondrial function by upregulating NAD + levels and activating silent information regulator 2 homolog 1 (SIRT1) in cardiomyocytes. Methods In vivo, 2% AKG was added to the drinking water of mice undergoing transverse aortic constriction (TAC) surgery. Echocardiography and biopsy were performed to evaluate cardiac function and pathological changes. Myocardial metabolomics was analyzed by liquid chromatography‒mass spectrometry (LC‒MS/MS) at 8 weeks after surgery. In vitro, the expression of SIRT1 or PINK1 proteins was inhibited by selective inhibitors and siRNA in cardiomyocytes stimulated with angiotensin II (AngII) and AKG. NAD + levels were detected using an NAD test kit. Mitophagy and ferroptosis levels were evaluated by Western blotting, qPCR, JC-1 staining and lipid peroxidation analysis. Results AKG supplementation after TAC surgery could alleviate myocardial hypertrophy and fibrosis and improve cardiac function in mice. Metabolites of the malate-aspartate shuttle (MAS) were increased, but the TCA cycle and fatty acid metabolism pathway could be inhibited in the myocardium of TAC mice after AKG supplementation. Decreased NAD + levels and SIRT1 protein expression were observed in heart of mice and AngII-treated cardiomyocytes. After AKG treatment, these changes were reversed, and increased mitophagy, inhibited ferroptosis, and alleviated damage in cardiomyocytes were observed. When the expression of SIRT1 was inhibited by a selective inhibitor and siRNA, the protective effect of AKG was suppressed. Conclusion Supplementation with AKG can improve myocardial hypertrophy, fibrosis and chronic cardiac insufficiency caused by pressure overload. By increasing the level of NAD + , the SIRT-PINK1 and SIRT1-GPX4 signaling pathways are activated to promote mitophagy and inhibit ferroptosis in cardiomyocytes, which ultimately alleviates cardiomyocyte damage.
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高影响因子
BIOMEDICINE & PHARMACOTHERAPY
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2024
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IF 6.9
Weikang Guo,Wanyue Wang,Fei Lei,Ruxin Zheng,Xinyao Zhao,Yuze Gu,Mengdi Yang,Yunshun Tong,Yaoxian Wang
Cisplatin (DDP) resistance poses a significant challenge in the treatment of ovarian cancer. Studies have shown that the combination of certain polysaccharides derived from plants with DDP is an effective approach to overcoming drug resistance in some cancers. Angelica sinensis (Oliv.) Diels has been used for centuries in China to treat gynecological ailments. Numerous studies indicate that Angelica sinensis polysaccharide (ASP), an extract from Angelica sinensis , can inhibit various forms of cancer. However, the impact of ASP on ovarian cancer remains unexplored. Through both in vitro and in vivo experiments, our study revealed the capability of ASP to effectively reversing DDP resistance in cisplatin-resistant ovarian cancer cells, while exhibiting acceptable safety profiles in vivo. To elucidate the mechanism underlying drug resistance reversal, we employed RNA-seq analysis and identified GPX4 as a key gene. Considering the role of GPX4 in ferroptosis, we conducted additional research to explore the effects of combining ASP with DDP on SKOV3/DDP cells. In summary, our findings demonstrate that the combination of ASP and DDP effectively suppresses GPX4 expression in SKOV3/DDP cells, thereby reversing their resistance to DDP.
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高影响因子
EUROPEAN JOURNAL OF PHARMACOLOGY
·
2021
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IF 4.432
Chiwei Peng,Xiang Fu,Kaixuan Wang,Ling Chen,Beijiao Luo,Ni Huang,Yunfeng Luo,Wei Chen
Intracerebral hemorrhage (ICH) is a severe stroke subtype with high disability and mortality, and no effective treatment is available. Previous research on intracerebral hemorrhage secondary brain injury drugs mainly targeted at cell apoptosis, inflammation and oxidative stress, but did not achieve good effects. In recent years, ferroptosis has become a focus concern in neurological diseases. Ferroptosis is a new type of programmed cell death caused by iron-dependent accumulation of lipid peroxides, in which glutathione peroxidase 4 (GPX4) is a key protein affecting ferroptosis. In this study, we used the STRING protein database to predict the proteins that may be co-expressed with GPX4, and studied the ability of Dauricine(Dau) to up-regulate the expression of GPX4 against ferroptosis and neuroprotection after intracerebral hemorrhage in normal cells in vitro, glutathione peroxidase 4 (GPX4) knockdown cells and collagenase injection in vivo in mouse models of intracerebral hemorrhage. The results showed that glutathione reductase (GSR) was a possible co-expression protein with GPX4. Dau could up-regulate the expression of glutathione peroxidase 4 (GPX4) in intracerebral hemorrhage(ICH) model, normal cells and GPX4 knockdown cells in vitro, and simultaneously up-regulate the expression of GSR in ICH mice. Dau could also reduce the levels of iron and lipid peroxidation, and have a neuroprotective effect on intracerebral hemorrhage(ICH) mice. It was tesified that Dauricine(Dau) could inhibit ferroptosis of nerve cells and alleviate brain injury after intracerebral hemorrhage by upregulating glutathione peroxidase 4 (GPX4) and glutathione reductase (GSR) co-expression. Therefore, Dau may be an effective drug for inhibiting ferroptosis and treating intracerebral hemorrhage.
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高影响因子
BIOCHEMICAL PHARMACOLOGY
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2022
·
IF 6.1
Meijie Chen,Xuena Li,Bulin Du,Song Chen,Yaming Li
Ferroptosis is considered as a potential target in cancer treatment including chemotherapy and radiotherapy, however, its regulatory mechanism on pancreatic cancer (PC) is not fully understood. Herein, we explored the role of upstream stimulatory factor 2 (USF2) and pyruvate kinase M2 (PKM2) in ferroptosis in PC cells. USF2 and PKM2 were highly expressed in PC tissues and USF2 was positively correlated with PKM2. PC cell lines BxpC-3 and AsPC-1 were transfected with small interfering RNAs against USF2/PKM2 or USF2 overexpressing plasmids or co-transfected with small interfering RNAs against PKM2 and USF2 overexpressing plasmids. Twenty-four hours after cell transfection, ferroptotic cell death was induced by incubation with 20 μmol/l erastin for 24 h. Ferroptotic cell death was promoted by USF2 knockdown and inhibited by USF2 overexpression. USF2 knockdown increased lipid reactive oxygen species and malonaldehyde generation and decreased glutathione concentration and glutathione peroxidase 4 expressions, indicating the enhanced lipid peroxidation. USF2 knockdown also increased ferrous iron levels and ferritin heavy chain expressions and reduced solute carrier family 7 member 11 expressions. However, USF2 overexpression reversed these changes. Furthermore, dual-luciferase reporter assay, chromatin immunoprecipitation assay and DNA pull down assay validated that USF2 transcriptionally regulated PKM2 expression through binding to its promoter. Interestingly, PKM2 also negatively regulated ferroptosis and PKM2 knockdown markedly impaired the effects of USF2 on lipid peroxidation and ferroptotic cell death. This study demonstrated that USF2 negatively regulated ferroptosis in PC cells through transcriptional regulation of PKM2, providing new evidences for uncovering the regulatory mechanism of ferroptosis on PC.
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高影响因子
PeerJ
·
2022
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IF 3.061
Tianyu Liu,Lei Yang,Hejun Gao,Yuzhen Zhuo,Zhengwei Tu,Yongqin Wang,Jing Xun,Qi Zhang,Lanqiu Zhang,Ximo Wang
APAP is one of the most commonly used antipyretic and pain medications, but excessive use can cause liver toxicity and damage. 3,4-dihydroxyphenylethyl alcohol glycoside (DAG) is a component isolated from Sargentodoxa cuneata known to have anti-apoptotic, anti-oxidation and anti-inflammatory effects. However, the effects of DAG on acute liver failure (ALF) are largely unknown. The purpose of this study is to study the protective effects and mechanism of DAG on APAP-induced ALF in mice. We established an ALF model in adult male pathogen-free C57BL/6 mice treated with APAP (300 mg/kg) by intraperitoneal injection and resolved by 24 h. Hematoxylin and eosin (HE) staining was used to evaluate the pathological changes in mouse liver tissue. The infiltration of neutrophils in liver tissue and reactive oxygen species (ROS) in AML12 cells were analyzed by flow cytometry. The levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), glutathione (GSH), malondialdehyde (MDA), catalase (CAT), and superoxide dismutase (SOD) were analyzed using relevant kits. Our results show that DAG reduced APAP-induced serum ALT and AST levels, histopathological changes, liver neutrophil infiltration and proinflammatory cytokines production, also attenuated the accumulation of MDA and the exhaustion of GSH, CAT and SOD. In vitro experiment indicated that DAG dose-dependently inhibited APAP-induced the levels of pro-inflammatory factors (IL-1β and IL18), and reactive oxygen species (ROS) and preventing GSH depletion in mouse AML12 hepatocytes. More interestingly, DAG inhibited the expression of ERK, HO-1, NLRP3, Caspase1 (p20) and Gasdermin-D and upregulated the expression of GPX4 in liver tissues and AML12hepatocytes. Therefore, our results indicate that DAG may act as a potential agent to treat ALF induced by APAP by inhibiting hepatocyte ferroptosis and pyroptosis.
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高影响因子
ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY
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2026
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IF 6.6
Shaowei Wang,Huiyi Che,Xiya Ren,Zi Lin,Zhuoqi Chen,Yang Zhu,Jingyun Chen,Yunbing Tang,Ren-shan Ge,Yingfen Ying
TEB induces GPX4-associated ferroptosis in human placental trophoblasts. • TEB impairs trophoblast proliferation, migration, and estradiol secretion. • Chorionic villi from RPL cases contain higher TEB levels than controls. • Integrated analyses link TEB exposure to ferroptosis and trophoblast dysfunction. Tebuconazole (TEB) is a widely used triazole fungicide with suspected endocrine-disrupting and reproductive toxicity. However, its effects on human placental trophoblasts and its association with unexplained recurrent pregnancy loss (RPL) remain poorly defined. Chorionic villi from 27 women with unexplained RPL and 25 women with normal pregnancies were analyzed by HPLC-MS/MS, and TEB effects were examined in BeWo and HTR-8/SVneo trophoblasts. Villus TEB residues were 1.82-fold higher in the RPL group (mean 0.0356 versus 0.0196 ng/g; P < 0.001), whereas TEB-OH did not differ significantly. In HTR-8/SVneo cells, 48-h TEB exposure reduced estradiol secretion at 20–80 µM and impaired migration at 40–80 µM without a significant loss of CCK-8 viability, and increased intracellular labile Fe 2 + . Transcriptome profiling at 80 µM identified 1680 differentially expressed genes (797 up-regulated, 883 down-regulated), and the downregulation of GPX4, TFRC, and SLC40A1 was confirmed by RT-qPCR and Western blotting. Network toxicology identified 72 core targets shared with RPL and fetal growth restriction, and docking predicted GPX4 as a candidate binding target of TEB (Ki= 44.74 µM). Consistent with a ferroptotic mechanism, ferrostatin-1 (2 µM) attenuated TEB-induced lipid peroxidation and Fe 2+ accumulation and partially restored GPX4, SLC40A1, and TFRC abundance, trophoblast migration, and estradiol secretion. These findings suggest that ferroptosis-related lipid peroxidation contributes to TEB-induced trophoblast dysfunction and links chorionic villus TEB residues to unexplained RPL. Because the effective in vitro concentrations exceed typical human exposure levels, the results provide mechanistic evidence of hazard and warrant further risk assessment. Download: Download high-res image (147KB) Download: Download full-size image
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高影响因子
Materials Today Bio
·
2026
·
IF 11
Bin Wang,Na Yin,Xinrui Liu,Yi Guan,Haiyang Xu,Ying Yu,Yang Bai,Yue Cao,Ziqian Wang,Shiqi Bai,Shaopeng Zhang,Donghao Qu,Wanying Li,Zhijia Lv,Yunqian Li,Hongquan Yu,Yinghui Wang
Glioma’s metabolic reprogramming fortifies antioxidant defenses and fosters an immunosuppressive microenvironment, thus resulting in robust resistance to ferroptosis-immunotherapy. In this study, a biomimetic sequentially gated amorphous MOF-based nanotuner (ZB@HM) was constructed, which could cascade depletion of metabolic substrates of ferroptosis defense and redistribution of methionine for reprogramming metabolism-ferroptosis-immunity crosstalk. Specifically, we engineered a methionine-inhibitor-loaded amorphous ZIF-82, followed by coating with E. coli-glioma hybrid membrane to improve its blood-brain barrier penetration and gliomas-targeting. The amorphous MOF undergoes acidic-triggered disintegration, releasing 2-nitroimidazole that is selectively activated via NADPH reduction in hypoxia. The activated ligand subsequently covalently binds with thiol-containing cysteine. The cascade depletion of NADPH and cysteine, synergizing with Zn 2+ overload, effectively triggers robust ferroptosis and immunogenic cell death. Moreover, ZB@HM selectively restricts methionine uptake in gliomas, suppressing the transsulfuration pathway for cysteine biosynthesis and enhancing the competitive uptake of methionine by T cells. The reduced intracellular methionine pool in gliomas diminishes S-adenosylmethionine biosynthesis, downregulating immune checkpoint expression. This cascade reverses T-cell exhaustion and reinforces antitumor immunity. RNA sequencing analysis revealed that treatment with ZB@HM resulted in a modulation of gene signatures associated with the GSH metabolism and tumor immunotherapy. Collectively, ZB@HM reprograms the metabolism-ferroptosis-immune crosstalk through orchestrating multiple key metabolites.
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高影响因子
PHYTOMEDICINE
·
2026
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IF 8.3
XiaoYang Qu,LiJuan Chen,JiangHua He,YuFei Fang,Jing Sun,ZhiYing Yu,Zhen Yang,ZiJing Zhang,JianBo Chen,Ling Dong
Background Epilepsy is a prevalent neurological disorder characterized by recurrent seizures and has limited effectiveness of available clinical treatments. Ferroptosis of neurons is one of the main mechanisms of epilepsy. Arisaema Cum Bile (ACB) is a traditional Chinese medicine that is prepared by fermenting animals bile with Rhizoma Arisaematis rhizomes, has demonstrated therapeutic effects on epilepsy and other nervous system diseases. Furthermore, the active components responsible for the anti-epileptic effects of ACB and the intrinsic mechanisms are still unclear. Purpose This study aims to clarify the principal bioactive constituents of ACB and their mechanisms in the treatment of epilepsy. It also seeks to provide data support for its clinical application in antiepileptic combination therapy. Method Pentylenetetrazol injections were used to induce epilepsy in rats. ACB and brain metabolites were identified via UPLC-Q-Exactive Orbitrap MS/MS, and active components were predicted through bioinformatics analysis. In vivo , ACB and hyodeoxycholic acid (HDCA) were administered by gavage, and the effects on oxidative stress, inflammation, and cognitive impairment were evaluated. Additionally, ferroptosis-related protein and gene expression were analyzed using western blot, PCR, immunofluorescence, and flow cytometry. In vitro , using primary neurons and HT22 cells, with electrophysiology employed to assess neuronal activity and glutamate used to induce ferroptosis in HT22 cells, in order to explore how HDCA alleviates epilepsy by inhibiting neuronal ferroptosis. Result A total of 37 chemical components were identified from the ACB, of which 10 active constituents can cross the blood-brain barrier, including steroids and terpenoids. Bioinformatics analysis suggests that HDCA may be one of the key active components responsible for ACB anti-epileptic effects and ferroptosis may represent a crucial underlying therapeutic mechanism. Studies in animals have demonstrated that treatment with ACB and HDCA reduced the frequency and severity of seizures in epileptic rats, mitigated hippocampal neuronal damage, improved post-epileptic cognitive learning capacity, alleviated neuroinflammatory injury and decreased markers of ferroptosis. This neuroprotective effect likely occurs through activation of the p53/Nrf2/GPX4 signaling pathway. Further in vitro cell experiments demonstrated that HDCA can inhibit the generation of action potentials in primary hippocampal neurons, protects HT22 neurons from glutamate-induced cell death, an effect that is reduced by Nrf2 inhibitors. These findings corroborate earlier bioinformatics analyses, confirming that the neuroprotective effects of HDCA are closely linked to Nrf2-mediated ferroptosis pathways. Conclusion HDCA is a key component of ACB anti-epileptic effects, potentially inhibiting ferroptosis through the p53/Nrf2/GPX4 pathway to reduce epilepsy.
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高影响因子
Nanoscale Horizons
·
2026
·
IF 6.6
Juxin Gao,Hengze Ding,Qinghua Wu,Yuhang Hu,Yifan Yan,Minming Chen,Chunjie Wang,Zhuang Liu,Liangzhu Feng
Ferroptosis, characterized by iron-dependent lipid peroxidation, represents a promising therapeutic target for cancer treatment. Strategies that disrupt intracellular antioxidant systems to induce ferroptosis in cancer cells have been extensively explored. Herein, we developed a pH-responsive phototheranostic agent (designed as FSB 4 Ca NPs) by encapsulating conjugated boron dipyrromethene tetramers (B4) within ferric ion-sulfasalazine metallo-network polymercoated calcium carbonate hollow nanoparticles. Sulfasalazine, a known ferroptosis inducer that inhibits System X c --mediated cysteine influx, synergizes with ferric ion-driven glutathione (GSH) depletion to collectively amplify intracellular lipid peroxidation. In addition to serving as a second near-infrared (NIR-II) fluorophore for tracking the in vivo distribution of FSB 4 Ca NPs, B4 mediates a photothermal effect that significantly enhances lipid peroxidation induction by boosting the Fenton catalytic activity of ferrous ions. Combined with localized 915-nm laser irradiation, intravenously administrated FSB 4 Ca NPs achieved substantial tumor suppression in mouse models, with a complete remission rate of 80%. This study establishes a facile strategy for developing long-circulating NIR-II phototheranostic agents with self-amplified lipid peroxidation induction capacity, enabling photothermally augmented ferroptosis for cancer therapy.
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高影响因子
EXPERIMENTAL CELL RESEARCH
·
2026
·
IF 3.5
Ruman Chen,Jiqing He,Na An,Mingzhi Xu,Liheng Wang,Yafei Bai
Background Vascular calcification (VC) is a severe cardiovascular complication of chronic kidney disease (CKD), driven by vascular smooth muscle cell (VSMC) osteogenic trans-differentiation and exacerbated by oxidative stress and cellular dysfunction. Despite its clinical relevance, the molecular mechanisms underlying CKD-associated VC remain incompletely understood. This study investigates the role of Sirtuin 1 (SIRT1) in modulating VC through ferroptosis inhibition and mitophagy activation and examines whether microRNA-181c-5p (miR-181c-5p) contributes to SIRT1 dysregulation in this context. Methods A CKD-associated VC model was induced in rats by 5/6 nephrectomy followed by high calcium/phosphate and calcitriol loading, and an in vitro calcification model was established in primary rat VSMCs. SIRT1 was manipulated using AAV9-mediated overexpression in vivo and plasmid overexpression or inhibition in vitro . Upstream regulation of SIRT1 by miR-181c-5p was predicted bioinformatically and validated by RNA pull-down and dual-luciferase assays. Ferroptosis was assessed by redox and Fe 2+ indices, and mitophagy by Pink1/Parkin, LC3-II and p62 expression. Rescue experiments employed erastin, Mdivi-1 and Parkin knockdown. Results SIRT1 expression was markedly reduced in calcified aortic tissues and VSMCs. SIRT1 overexpression suppressed VC by reducing calcium deposition, downregulating osteogenic markers, and increasing fetuin-A levels. SIRT1 also suppressed ferroptosis by restoring the GSH/GPX4/SLC7A11 axis and limiting ROS and lipid peroxidation, whereas erastin abolished these effects. Mechanistically, miR-181c-5p was found to directly target SIRT1 and promote VSMC calcification by repressing SIRT1. Moreover, SIRT1 promoted mitophagy via the Pink1/Parkin pathway activation. Furthermore, inhibition of mitophagy reversed the anti-ferroptotic effects of SIRT1, confirming their functional interplay. Conclusions SIRT1, negatively regulated by miR-181c-5p, mitigates CKD-associated VC by suppressing ferroptosis and activating Pink1/Parkin-dependent mitophagy in VSMCs, highlighting a potential therapeutic axis for vascular protection in CKD. Clinical trial registration number Not applicable.
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