Frontiers in Pharmacology
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2023
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IF 5.6
Fangze Huang,Ximao Liu,Junjie Liu,Yu Xie,Li Zhao,Deshen Liu,Zifeng Zeng,Xiu Liu,Shaoyi Zheng,Zezhou Xiao
As atrial fibrosis is the main feature of atrial structural remodeling, inhibiting atrial fibrosis is crucial to the prevention of atrial fibrillation (AF) progression. Research has shown the correlation between abnormal lipid metabolism and AF progression. However, the effect of specific lipids on atrial fibrosis remains unclear. In the present study, we applied ultra-high-performance lipidomics to analyze the lipid profiles in patients with AF and identify phosphatidylethanolamine (PE) as the differential lipid associated with AF. To detect the effect of the differential lipid on atrial fibrosis, we performed the intraperitoneal injection of Angiotensin II (Ang II) to mice to induce atrial fibrosis and supplemented PE in diets. We also treated atrial cells with PE to evaluate the cellular effect of PE. We found that PE supplementation aggravated atrial fibrosis and increased the expression of the fibrosis-related protein in vitro and in vivo . Moreover, we detected the effect of PE on the atrium. We found that PE increased oxidation products and regulated the expression of ferroptosis-related proteins, which could be alleviated by a ferroptosis inhibitor. PE increased peroxidation and mitochondrial damage in vitro , which promoted cardiomyocyte death induced by Ang II. Examination of protein expression in cardiomyocytes indicated that PE triggered ferroptosis and caused cell death to participate in myocardium fibrosis. In summary, our findings demonstrated the differential lipid profiles of AF patients and revealed the potential effect of PE on atrial remodelling, suggesting that inhibition of PE and ferroptosis might serve as a potential therapy to prevent AF progression.
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Frontiers in Pharmacology
·
2026
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IF 5.4
Haifeng Hu,Wenting Zhang,Huilong Wang,Shengpeng Zhang,Shaozhen Wang,Yuewu Xie
Introduction Cisplatin (CIS)-induced nephrotoxicity is a dose-limiting adverse effect that hinders its clinical efficacy. Artesunate (ART) exerts well-documented anti-inflammatory and anti-oxidative effects, but its potential efficacy against CIS-induced nephrotoxicity remains poorly elucidated. Methods The renoprotective effects of ART were evaluated in a murine CIS-induced nephrotoxicity model and human HK-2 renal tubular epithelial cells. Renal function, histopathological injury, inflammation, and oxidative stress were evaluated. Untargeted renal metabolomics and transcriptomics were integrated to identify potential pathways, followed by targeted biochemical and molecular validation. Indoxyl sulfate rescue experiments were performed to investigate the functional relationship between tryptophan metabolism and ferroptosis. Results ART treatment significantly ameliorated CIS-induced renal dysfunction, as evidenced by reduced SCr and BUN levels and attenuated histopathological damage. These functional improvements were accompanied by marked suppression of pro-inflammatory cytokines and restoration of redox balance. Integrated renal metabolomic and transcriptomic analyses revealed that ART exerts its protective effects primarily through modulation of tryptophan metabolism and ferroptosis pathway. Subsequent validation confirmed that ART inhibited ferroptosis by reducing Fe 2+ accumulation, downregulating ACSL4 and FTL, and upregulating GPX4 and xCT. In HK-2 cells, indoxyl sulfate partially counteracted the cytoprotective and anti-ferroptotic effects of ART. Moreover, ART did not diminish CIS’s antineoplastic effect in human cancer cells. Conclusion These findings demonstrate that ART alleviates CIS-induced nephrotoxicity by restoring tryptophan metabolic homeostasis and suppressing ferroptosis, positioning ART as a promising therapeutic candidate for preventing nephrotoxicity in patients undergoing CIS chemotherapy.
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Journal of Environmental Sciences
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2026
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IF 6.5
Xiaoyan Li,Ying Cheng,Zhuling Xu,Runfeng Chang,Jin Yan,Zejun Wang,Xuedong Wang,Huili Wang,Qiuhui Qian
● AgNPs disrupted hepatic lipid metabolism and induced ferroptosis-related toxicity. ● AgNPs induced SCD1 upregulation associated with lipid dysregulation and ferroptosis. ● SCD1 may link lipid metabolism with PPARγ pathway and ferroptosis-related injury. ● AgNPs exposure was associated with insulin resistance– and T2DM-like alterations. Silver nanoparticles (AgNPs) are widely used nanomaterials, yet their potential metabolic and hepatic risks remain insufficiently understood. In this study, we investigated the toxicological effects of AgNPs in zebrafish and explored the potential involvement of a peroxisome proliferator-activated receptor γ (PPARγ)–stearoyl-CoA desaturase 1 (SCD1)–ferroptosis–related pathway associated with lipid metabolic disturbance and type 2 diabetes mellitus (T2DM)-like metabolic alterations. AgNPs exposure induced coordinated upregulation of PPARγ and SCD1 and downregulation of glutathione peroxidase 4 (GPX4), which were accompanied by hepatic lipid accumulation, oxidative stress, and ferroptosis-related responses in larvae, as indicated by elevated reactive oxygen species (ROS) and Fe 2+ levels, glutathione (GSH) depletion, and enhanced lipid peroxidation. These alterations persisted into adulthood and were accompanied by increased body and liver weight, dyslipidemia, hyperglycemia, and impaired insulin signaling, resembling T2DM-like phenotypes. Pharmacological inhibition further supported the involvement of this pathway: the ferroptosis inhibitor deferoxamine (DFO), the PPARγ antagonist 2-chloro-5-nitro-N-(pyridin-4-yl)benzamide (T0070907), and the SCD1 inhibitor 4-(2-chlorophenoxy)-N-[3-[(methylamino)carbonyl]phenyl]-1-piperidinecarboxamide (A939572) significantly alleviated AgNPs-associated hepatic injury. Mechanistic analyses suggest that SCD1, acting downstream of PPARγ, may function as a key mediator linking lipid metabolic dysregulation to ferroptosis. Collectively, these findings provide new insight into the metabolic toxicity associated with AgNPs exposure and contribute to improved ecological and biomedical safety assessment of engineered nanomaterials. Download: Download high-res image (382KB) Download: Download full-size image
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Redox Biology
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2023
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IF 11.4
Zhi Xu,Xiumei Wang,Wenbo Sun,Fan Xu,Hengyuan Kou,Weizi Hu,Yanyan Zhang,Qin Jiang,Jinhai Tang,Yong Xu
Tamoxifen (TAM) resistance remains a major obstacle in the treatment of advanced breast cancer (BCa). In addition to the competitive inhibition of the estrogen receptor (ER) signaling pathway, damping of mitochondrial function by increasing reactive oxygen species (ROS) is critical for enhancing TAM pharmacodynamics. Here, we showed that RelB contributes to TAM resistance by inhibiting TAM-provoked ferroptosis. TAM-induced ROS level promoted ferroptosis in TAM-sensitive cells, but the effect was alleviated in TAM-resistant cells with high constitutive levels of RelB. Mechanistically, RelB inhibited ferroptosis by transcriptional upregulating glutathione peroxidase 4 (GPX4). Consequently, elevating RelB and GPX4 in sensitive cells increased TAM resistance, and conversely, depriving RelB and GPX4 in resistant cells decreased TAM resistance. Furthermore, suppression of RelB transcriptional activation resensitized TAM-resistant cells by enhancing ferroptosis in vitro and in vivo . The inactivation of GPX4 in TAM-resistant cells consistently resensitized TAM by increasing ferroptosis-mediated cell death. Together, this study uncovered that inhibition of ferroptosis contributes to TAM resistance of BCa via RelB-upregulated GPX4.
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BIOMATERIALS
·
2023
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IF 14
Jiaxin Zhang,Kaicheng Zhou,Jingbo Lin,Xianxian Yao,Dianwen Ju,Xian Zeng,Zhiqing Pang,Wuli Yang
Triple-negative breast cancer (TNBC) causes great suffering to patients because of its heterogeneity, poor prognosis, and chemotherapy resistance. Ferroptosis is characterized by iron-dependent oxidative damage by accumulating intracellular lipid peroxides to lethal levels, and plays a vital role in the treatment of TNBC based on its intrinsic characteristics. To identify the relationship between chemotherapy resistance and ferroptosis in TNBC, we analyzed the single cell RNA-sequencing public dataset of GSE205551. It was found that the expression of Gpx4 in DOX-resistant TNBC cells was significantly higher than that in DOX-sensitive TNBC cells. Based on this finding, we hypothesize that inducing ferroptosis by inhibiting the expression of Gpx4 can reduce the resistance of TNBC to DOX and enhance the therapeutic effect of chemotherapy on TNBC. Herein, dihydroartemisinin (DHA)-loaded polyglutamic acid-stabilized Fe 3 O 4 magnetic nanoparticles (Fe 3 O 4 -PGA-DHA) was combined with DOX-loaded polyaspartic acid-stabilized Fe 3 O 4 magnetic nanoparticles (Fe 3 O 4 -PASP-DOX) for ferroptosis-enhanced chemotherapy of TNBC. Compared with Fe 3 O 4 -PASP-DOX, Fe 3 O 4 -PGA-DHA + Fe 3 O 4 -PASP-DOX demonstrated significantly stronger cytotoxicity against different TNBC cell lines and achieved significantly more intracellular accumulation of reactive oxygen species and lipid peroxides. Furthermore, transcriptomic analyses demonstrated that Fe 3 O 4 -PASP-DOX-induced apoptosis could be enhanced by Fe 3 O 4 -PGA-DHA-induced ferroptosis and Fe 3 O 4 -PGA-DHA + Fe 3 O 4 -PASP-DOX might trigger ferroptosis in MDA-MB-231 cells by inhibiting the PI3K/AKT/mTOR/GPX4 pathway. Fe 3 O 4 -PGA-DHA + Fe 3 O 4 -PASP-DOX showed superior anti-tumor efficacy on MDA-MB-231 tumor-bearing mice, providing great potential for improving the therapeutic effect of TNBC.
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JOURNAL OF COLLOID AND INTERFACE SCIENCE
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2023
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IF 9.9
Minyi Zhang,Ying Chen,Qi Wang,Chunlin Li,Chunping Yuan,Jie Lu,Yu Luo,Xijian Liu
The reactive oxygen species (ROS) produced through the Fenton reaction , induces lipid peroxide (LPO), causing cellular structural damage and ultimately triggering ferroptosis. However, the generation of ROS in the tumor microenvironment (TME) is limited by the catalytic efficiency of the Fenton reaction. Herein, a novel hollow mesoporous silica nanoparticle (HMSN) combined with multi-metal sulfide-doped mesoporous silica nanocatalyzers (NCs) was developed, namely M x S y -HMSN NCs (M represents Cu Mn and Fe, S denotes sulfur). The M x S y -HMSN can dramatically enhanced the ferroptosis by: (1) facilitating the conversion of H 2 O 2 to ·OH through Fenton or Fenton-like reactions through co-catalysis; (2) weakening ROS scavenging systems by depleting the over expressed glutathione (GSH) in TME; (3) providing exceptional photothermal therapy to augment ferroptosis. The M x S y -HMSN can also act as smart cargos for anticancer drug-doxorubicin (DOX). The release of DOX is responsive to GSH/pH/Near-infrared Light (NIR) irradiation at the tumor lesion, significantly improving therapeutic outcomes while minimizing side effects. Additionally, the M x S y -HMSN has demonstrated excellent magnetic resonance imaging (MRI) potential. This smart M x S y -HMSN offer a synergetic approach combining ferroptosis with chemo-photothermal therapy and magnetic resonance imaging (MRI) diagnose, which could be an informative guideline for the design of future NCs.
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ACS Nano
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2023
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IF 17.1
Jiajia Luo,Yao Li,Yaru Li,Xuefei Chen,Panyu Du,Zheng Wang,Aixian Tian,Yanjun Zhao
Ferroptotic cancer therapy is promising in many scenarios where traditional cancer therapies show a poor response. However, certain types of cancers lack the long-chain acyl-CoA synthetase 4 (ACSL4), a key modulator of ferroptosis, resulting in therapy resistance and tumor relapse. Because ACSL4 is in charge of the synthesis of ferroptotic lipids (e.g., arachidonoylphosphatidylethanolamine/PE-AA), we postulated that direct delivery of PE-AA may reverse ferroptosis resistance induced by ACSL4 deficiency. To further increase the ferroptosis sensitivity, we employed the ferrocene-bearing polymer micelles to co-load PE-AA with an FDA-approved redox modulator, auranofin (Aur), targeting the thioredoxin reductase. The presence of ferrocene enabled triggered cargo release and iron production, which can sensitize ferroptosis by boosting autoxidation-mediated PE-AA peroxidation. The micellar system could impair redox homeostasis and induce lipid peroxidation in ACSL4-deficient MCF-7 cells. Moreover, the tailored micelles potently induced ferroptosis in MCF-7 tumors in vivo, suppressed tumor growth, and increased the mice’s survival rate. The current work provides a facile means for reversing the ferroptosis resistance in ACSL4-deficient tumors.
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JOURNAL OF NANOBIOTECHNOLOGY
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2023
·Vol. 21
·期 1
·1-12
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IF 10.2
Wang Jianxin,Chu Yinzhu,Zhao Zhiyu,Zhang Cong,Chen Qi,Ran Haitao,Cao Yang,Wu Changjun
Graphdiyne has excellent potential due to its enzymatic properties. Metal-free sulfur-doped Graphdiyne (S-GDY) has piezoelectric characteristics, and ultrasonic excitation of S-GDY enhances peroxidase activity. It can turn hydrogen peroxide into toxic hydroxyl radicals and induce apoptosis in 4T1 cells. More importantly, the ultrasound (US) enhanced nanozyme induced 4T1 cell ferroptosis by promoting an imbalanced redox reaction due to glutathione depletion and glutathione peroxidase 4 inactivation. S-GDY exhibited enhanced nanozyme activity in vitro and in vivo that may directly trigger apoptosis-ferroptosis for effective tumor therapy. Altogether, this study was expected to provide new insights into the design of piezoelectric catalytic nanozyme and expand their application in the catalytic therapy of tumors.Graphical Abstract
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Materials Today Bio
·
2024
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IF 8.7
Yiting Chen,Xinhong Li,Kuankuan Luo,Tao Wang,Tongyao Liu,Enhao Lu,Rui Wang,Yu Luo,Xianyi Sha
Breast cancer is the most diagnosed malignancy in women globally, and drug resistance is among the major obstacles to effective breast cancer treatment. Emerging evidence indicates that photothermal therapy and ferroptosis are both promising therapeutic techniques for the treatment of drug-resistant breast tumors. In this study, we proposed a thermal/ferroptosis/magnetic resonance imaging (MRI) triple functional nanoparticle (I@P-ss-FRT) in which ferritin, an iron storage material with excellent cellular uptake capacity, was attached via disulfide bonds onto polydopamine coated iron oxide nanoparticle (I@P) as photothermal transduction agent and MRI probe. I@P-ss-FRT converted the near-infrared light (NIR) into localized heat which accelerated the release of ferrous ions from ferritin accomplished by glutathione reduction and subsequently induced ferroptosis. The drug-resistant cancer cell lines exhibited a more significant uptake of I@P-ss-FRT and sensitivity to PTT/ferroptosis compared with normal cancer cell lines. In vivo , I@P-ss-FRT plus NIR displayed the best tumor-killing potential with inhibitory rate of 83.46 %, along with a decline in GSH/GPX-4 content and an increase in lipid peroxides generation at tumor sites. Therefore, I@P-ss-FRT can be applied to combat drug-resistant breast cancer.
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MOLECULAR NEUROBIOLOGY
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2024
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IF 4.6
Shi Haoyu,Song Libiao,Wu Yonghui,Shen Ruonan,Zhang Chenxu,Liao Xingzhi,Wang Qiuhong,Zhu Jie
Traumatic brain injury (TBI) is a highly severe form of trauma with complex series of reactions in brain tissue which ultimately results in neuronal damage. Previous studies proved that neuronal ferroptosis, which was induced by intracranial haemorrhage and other reasons, was one of the most primary causes of neuronal damage following TBI. However, the association between neuronal mechanical injury and ferroptosis in TBI and relevant treatments remain unclear. In the present study, we first demonstrated the occurrence of neuronal ferroptosis in the early stage of TBI and preliminarily elucidated that edaravone (EDA), a cerebroprotective agent that eliminates oxygen radicals, was able to inhibit ferroptosis induced by TBI. A cell scratching model was established in PC12 cells, and it was confirmed that mechanical injury induced ferroptosis in neurons at the early stage of TBI. Ferroptosis suppressor protein 1 (FSP1) plays a significant role in inhibiting ferroptosis, and we found that iFSP, a ferroptosis agonist which is capable to inhibit FSP1 pathway, attenuated the anti-ferroptosis effect of EDA. In conclusion, our results suggested that EDA inhibited neuronal ferroptosis induced by mechanical injury in the early phase of TBI by activating FSP1 pathway, which could provide evidence for future research on prevention and treatment of TBI.
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JOURNAL OF NANOBIOTECHNOLOGY
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2025
·Vol. 23
·期 1
·1-20
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IF 12.6
Gu Lina,Sun Ying,Bai Tingjie,Shao Sijie,Tang Shumin,Xue Panpan,Cai Wanlin,Qin Xian,Zeng Xuemei,Yan Shuangqian
Elevated copper levels induce tumor cuproptosis and ferroptosis, leading to immunogenic cell death and subsequent antitumor immune responses. However, dysregulated copper metabolism in tumor cells maintains homeostatic copper balance, while hypoxic microenvironments hinder therapeutic efficacy. In this study, we present a nanozyme system, termed Cu ss OMEp, comprising a copper-based nanovector (Cu ss NV) that is PEGylated and loaded with omeprazole, a copper transporter inhibitor, to enhance tumor synergistic immunotherapy by promoting cuproptosis and ferroptosis. Cu ss NV is assembled from dithiodiglycolic acid and copper ions, exhibiting peroxidase, glutathione oxidase, and catalase-like activities, along with responsive degradability. This nanozyme alleviates tumor hypoxia by producing oxygen, induces ferroptosis through the generation of lethal hydroxyl radicals, and depletes glutathione. Additionally, omeprazole increases cellular copper concentration and oxidative stress by inhibiting the intracellular copper-transporting ATPase 1 (ATP7A), enhancing lipoylated protein oligomerization and cuproptosis. In a breast tumor mouse model, Cu ss OMEp elicits robust antitumor immune responses, including dendritic cell maturation and T cell proliferation. When combined with PD-1 antibodies (αPD-1), Cu ss OMEp significantly inhibits tumor metastasis in bilateral and lung metastatic models. This work presents a functional nanozyme system as a promising strategy for synergistic tumor immunotherapy leveraging ferroptosis and cuproptosis Graphical abstract
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INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
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2024
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IF 7.7
Yizhi Wang,Jiawen Han,Shifang Zhan,Chenyu Guo,Shuangneng Yin,Lin Zhan,Qianyi Zhou,Ruiying Liu,Hua Yan,Xiaoyan Wang,Dan Yan
Doxorubicin (Dox), a chemotherapeutic agent frequently used to treat cancer, elicits cardiotoxicity, a condition referred to as Dox-induced cardiotoxicity (DIC), and ferroptosis plays a contributory role in its pathophysiology. Fucoidan, a polysaccharide with various biological activities and safety profile, has potential therapeutic and pharmaceutical applications. This study aimed to investigate the protective effects and underlying mechanisms of fucoidan in DIC. Echocardiography, biomarkers of cardiomyocyte injury, serum creatine kinase, creatine kinase isoenzyme and lactate dehydrogenase, as well as histological staining results, revealed that fucoidan significantly reduced myocardial damage and improved cardiac function in DIC mice. Transmission electron microscopy; levels of lipid reactive oxygen species, glutathione, and malondialdehyde; ferroptosis-related markers; and regulatory factors such as glutathione peroxidase 4 (GPX4), transferrin receptor protein-1, ferritin heavy chain-1, heme oxygenase-1 in the heart tissue were measured to explore the effect of fucoidan on Dox-induced ferroptosis. These results suggested that fucoidan could inhibit cardiomyocyte ferroptosis caused by Dox. In vitro experiments revealed that silencing nuclear factor-erythroid 2-related factor 2 (Nrf2) in cardiomyocytes reduced the inhibitory effect of fucoidan on ferroptosis. Hence, fucoidan has the potential to ameliorate DIC by inhibiting ferroptosis via the Nrf2/GPX4 pathway.
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