ENVIRONMENTAL TOXICOLOGY
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2022
·Vol. 37
·期 9
·2201-2213
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IF 4.109
Qi Xiong,Xiang Tian,Congyue Xu,Baomiao Ma,Wei Liu,Binlian Sun,Qin Ru,Xiji Shu
PM 2.5 exposure has been demonstrated to correlate with neurological disorders recently. Ferroptosis is recognized as a newly found programmed form of cell death associated with neurodegenerative diseases, while glutathione peroxidase 4 (GPX4) is a key regulator of ferroptosis. However, the relationship between PM 2.5 -induced neurotoxicity and ferroptosis is still unclear. The current study aims to investigate if ferroptosis is involved in neurotoxicity post PM 2.5 exposure and its underlying mechanism. The PM 2.5 -treated neuronal Neuro-2a (N2A) and SH-SY5Y cells were applied to the current study. The results showed that PM 2.5 significantly increased the neuronal cell death, yet the ferroptosis antagonist Ferrostain-1 (Fer-1) markedly decreased the cell death induced by PM 2.5 . Western blot further confirmed that ferroptosis was triggered post PM 2.5 treatment in N2A cells by decreasing expressions of GPX4 and ferritin heavy chain (FTH), as well as enhancing expressions of ferritin light chain (FTL) and transferrin receptor protein (TFRC). Meanwhile, PM 2.5 treatment augmented neuronal oxidative damage and mitochondrial dysfunction. The bioinformatic analysis indicated that CREB could be the regulator of GPX4, and our results showed that ERK/CREB pathway was down-regulated in N2A cells post PM 2.5 treatment. The addition of ERK1/2 agonist post PM 2.5 treatment significantly inhibit ferroptosis via increasing the expression of GPX4. Taken together, the present study demonstrated that PM 2.5 -induced ferroptosis via inhibiting ERK/CREB pathway, and these findings will advance our knowledge of PM 2.5 -induced cytotoxicity in the nervous system.
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iScience
·
2022
·
IF 6.107
Kun Fang,Sha Du,Dachuan Shen,Zhipeng Xiong,Ke Jiang,Dapeng Liang,Jianxin Wang,Huizhe Xu,Lulu Hu,Xingyue Zhai,Yuting Jiang,Zhiyu Xia,Chunrui Xie,Di Jin,Wei Cheng,Songshu Meng,Yifei Wang
Summary Ferroptosis is a new kind of regulated cell death that is characterized by highly iron-dependent lipid peroxidation. Cancer cells differ in their sensitivity to ferroptosis. Here we showed that the Suppressor of fused homolog (SUFU), a critical component in Hedgehog signaling, regulates ferroptosis sensitivity of breast cancer cells. Ectopic SUFU expression suppressed, whereas depletion of SUFU enhanced the sensitivity of breast cancer cells to RSL3-triggered ferroptosis through deregulation of ACSL4. Moreover, SUFU depletion promoted the activation of Yes-associated protein (YAP), thereby increasing the expression of ACSL4. Mechanistically, SUFU is associated with LATS1. Deletion of a region comprising residues 174–385 in SUFU disrupted SUFU binding to LATS1, thus abrogating SUFU-mediated downregulation of the YAP-ACSL4 axis and sensitivity to ferroptosis. Noteworthy, we showed that vincristine downregulated SUFU, thus increasing breast cancer cell sensitivity to RSL3 in vitro and in vivo . Together, our findings uncover SUFU as a novel regulator in ferroptosis sensitivity.
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Bioactive Materials
·
2021
·
IF 14.593
Haibao Peng,Xingcai Zhang,Peng Yang,Jiaxu Zhao,Wei Zhang,Nianping Feng,Wuli Yang,Jing Tang
The emergence of multidrug treatment resistance presents a hurdle for the successful chemotherapy of tumours. Ferroptosis, resulting from the iron-dependent accumulation of lipid peroxides, has the potential to reverse multidrug resistance. However, simultaneous delivery of the iron sources, ferroptosis inducers, drugs, and enhanced circulation carriers within matrices remains a significant challenge. Herein, we designed and fabricated a defect self-assembly of metal-organic framework (MOF)-red blood cell (RBC) membrane-camouflaged multi-drug-delivery nanoplatform for combined ferroptosis-apoptosis treatment of multidrug-resistant cancer. Ferroptosis and chemotherapeutic drugs are embedded in the centre of the iron (III)-based MOF at defect sites by coordination with metal clusters during a one-pot solvothermal synthesis process. The RBC membrane could camouflage the nanoplatform for longer circulation. Our results demonstrate that this defect self-assembly-enabled MOF-membrane-camouflaged nanoplatform could deplete the glutathione, amplify the reactive oxidative species oxidative stress, and enable remarkable anticancer properties. Our work provides an alternative strategy for overcoming multidrug resistance, which could regulate the fluidity and permeability of the cell membrane by ferroptosis to downregulate of P -glycoprotein protein expression by ferroptosis. This defect self-assembly-enabled MOF-membrane-camouflaged multi-drug-delivery nanoplatform has great therapeutic potential.
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Cell Death & Disease
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2022
·Vol. 13
·期 11
·1-12
·
IF 9.685
Hu Xiaomeng,He Yuchao,Han Zhiqiang,Liu Wei,Liu Dongming,Zhang Xihao,Chen Lu,Qi Lisha,Chen Liwei,Luo Yi,Li Qiang,Chen Peng,Wu Qiang,Zhu Xiaolin,Guo Hua
Effective strategies for hepatocellular carcinoma, which is the second leading cause of death worldwide, remain limited. A growing body of emerging evidence suggests that ferroptosis activation is a novel promising approach for the treatment of this malignancy. Nevertheless, the potential therapeutic targets and molecular mechanisms of ferroptosis remain elusive. In this study, we found that PNO1 is a bona fide inhibitor of ferroptosis and that autophagy induced by PNO1 promotes cystine/glutamate antiporter SLC7A11 while increasing the synthesis and accumulation of intracellular glutamate. This increase is followed by an equally proportional addition in cystine uptake, which consequently enhances system Xc - activity that leads to the inhibition of ferroptosis. In the maintenance of redox homeostasis, system Xc - activated via PNO1-autophagy metabolism is responsible for maintaining cysteine for glutathione (GSH) synthesis, and the final GSH metabolic reprogramming protects HCC cells from ferroptosis. The combination of PNO1 inhibition with drugs causing ferroptosis induction, particularly sorafenib, the first-line drug associated with ferroptosis in liver cancer shows therapeutic promise in vitro and in vivo. Together, our findings indicated that PNO1 protects HCC cells from ferroptotic death through autophagy-mediated GSH metabolic remodeling, and we identified a candidate therapeutic target that may potentiate the effect of ferroptosis-based antitumor therapy.
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Bioactive Materials
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2022
·
IF 16.874
Chang Liu,Quan Zou,Huixin Tang,Jia Liu,Shiqi Zhang,Caihong Fan,Junwei Zhang,Ruiqing Liu,Yashan Liu,Ruiyan Liu,Yan Zhao,Qiang Wu,Zhi Qi,Yanna Shen
Myocardial injury as one of the severe complications leads to the increasing morbidity and mortality in patients with sepsis. Recent studies reported that reactive oxygen species (ROS)-mediated ferroptosis plays a critical role in the development of heart diseases. Therefore, we hypothesized that anti-ferroptosis agent might be a novel potential therapeutic strategy for sepsis-induced cardiac injury. Herein, we demonstrated that a small biocompatible and MRI-visible melanin nanoparticles (MMPP) improves myocardial function by inhibiting ROS-related ferroptosis signaling pathway. In LPS-induced murine sepsis model, after a single dose intravenously injection of MMPP treatment, MMPP markedly alleviated the myocardial injury including cardiac function and heart structure disorder through suppressing iron-accumulation induced ferroptosis. In vitro , MMPP inhibited cardiomyocyte death by attenuating oxidative stress, inflammation and maintaining mitochondrial homeostasis. Collectively, our findings demonstrated that MMPP protected heart against sepsis-induced myocardial injury via inhibiting ferroptosis and inflammation, which might be a novel therapeutic approach in future.
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Frontiers in Pharmacology
·
2026
·
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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ACS Nano
·
2023
·
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 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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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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Redox Biology
·
2023
·
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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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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