Cell and Bioscience
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2023
·Vol. 13
·期 1
·1-15
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IF 7.5
Zhao Hongting,Zhang Meng,Zhang Jinghua,Sun Zichen,Zhang Wenxin,Dong Weichen,Cheng Chen,Yao Yongzhong,Li Kuanyu
Background Ferroptosis is a unique cell death, dependent on iron and phospholipid peroxidation, involved in massive processes of physiopathology. Tremendous attention has been caught in oncology, particularly for those therapy-resistant cancers in the mesenchymal state prone to metastasis due to their exquisite vulnerability to ferroptosis. Therefore, a therapeutical ferroptosis inducer is now underway to be exploited.Results A natural compound, hinokitiol (hino), has been considered to be an iron chelator. We have a novel finding that hino complexed with iron to form Fe(hino)3 can function as a ferroptosis inducer in vitro. The efficiency, compared with the same concentration of iron, increases nearly 1000 folds. Other iron chelators, ferroptosis inhibitors, or antioxidants can inhibit Fe(hino)3-induced ferroptosis. The complex Fe(hino)3 efficacy is further confirmed in orthotopic triple-negative breast cancer (TNBC) tumor models that Fe(hino)3 significantly boosted lipid peroxidation to induce ferroptosis and significantly reduced the sizes of TNBC cell-derived tumors. The drug’s safety was also evaluated, and no detrimental side effects were found with the tested dosage.Conclusion sWhen entering cells, the chelated iron by hinokitiol as a complex Fe(hino)3 is proposed to be redox-active to vigorously promote the production of free radicals via the Fenton reaction. Thus, Fe(hino)3 is a ferroptosis inducer and, therapeutically, exhibits anti-TNBC activity.
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CHEMICAL ENGINEERING JOURNAL
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2023
·
IF 15.1
Kai Sun,Jiaying Yu,Jinzhong Hu,Wanxiang Yang,Xianfeng Chu,Lucheng Chen,Xiongwei Deng,Baiwang Sun,Zhifei Wang
Ferroptosis is an emerging antitumor treatment modality with the superiority for evading apoptotic cell death pathway. However, how to elevate catalytic efficacy of Fe 2+ -mediated Fenton reaction and efficiently elicit ferroptosis remain enormously challenging. Herein, inspired by hyperthermia-enhanced Fenton reaction kinetics, we firstly designed iron-polyphenol-aspirin-coordinated nanochelates for photothermal-enhanced ferroptosis antitumor immunotherapy. Specifically, we modulated optimal mass feeding ratio of gallic acid (GA), aspirin (ASA), Fe (II) and polyvinylpyrrolidone (PVP) to construct novel nanofibrous GA-ASA-Fe (II) metalchelates named GAFs. The variations in size and structure allowed the nanomedicines to avoid the risk of premature renal clearance in vivo, compared with the reported ultrasmall GA-Fe (II) nanocomplexes (GFs). Under NIR laser irradiation, GAFs could constantly amplify toxic hydroxyl radicals ( OH) generation and deplete excessive GSH to induce more accumulation of lethal lipid peroxidation (LPO), thereby triggering ferroptosis pathway in vitro and in vivo. Besides, the introduction of ASA could inhibit cyclooxygenase-2 (COX-2) and prostaglandin E 2 (PGE 2 ), in combination with photothermal-enhanced ferroptosis tumor therapy to induce immunogenic cell death (ICD), promote maturation of dendritic cells (DCs) and activate cytotoxic T cells for synergistic antitumor immunotherapy. GAFs with laser irradiation exhibited the capacity of inhibition of pulmonary metastasis. This work presented a strategy for incorporating small molecule immunomodulator into the metal-polyphenolic coordination to ameliorate its deficiencies, thereby inspiring a new design concept for tumor treatment.
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Nano Today
·
2023
·
IF 17.4
Ting Song,Geng Yang,Hanxi Zhang,Mengyue Li,Wanyi Zhou,Chuan Zheng,Fengming You,Chunhui Wu,Yiyao Liu,Hong Yang
Ferroptosis is an iron-dependent form of cell death that is also a promising tumor therapeutic modality, however, maintaining redox and iron homeostasis in tumor cells limits the ferroptosis therapeutic effect. Herein, we constructed a GSH-depleting magnetic nanoplatform ( [email protected] ) for enhanced ferroptosis by disruption of redox homeostasis and ferritinophagy-mediated iron disorders. [email protected] was constructed by coating disulfide bonds-bridged mesoporous silica shells on magnetic nanoparticles (MNPs) and loaded with dihydroartemisinin (DHA, ROS precursor drug). Upon endocytosis by tumor cells, disulfide bond-mediated glutathione depletion and glutathione peroxidase 4 (GPX4) inactivation will synergize with DHA to disrupt intracellular redox homeostasis. On the other hand, the magnetic hyperthermia generated by [email protected] will trigger ferritinophagy to achieve tumor iron dyshomeostasis and enhance ferroptosis. Moreover, the released ferrous ions can activate DHA to produce ROS and further disrupt redox homeostasis. Both in vitro and in vivo results demonstrated that [email protected] can significant suppression of tumor growth with minimal side effects through the disturbance of dual homeostasis and the intense ferroptosis of tumor cells. Furthermore, MNPs could also provide excellent T 2 -weighted MR imaging properties. In this work, magnetic hyperthermia was first proven to trigger autophagy-augmented ferroptosis, and the strategies through multi-pathway intracellular homeostasis disruption described in this article can offer an innovative approach in ferroptosis-based antitumor .
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ACS Nano
·
2023
·
IF 17.1
Lijuan Zeng,Shuaishuai Ding,Yuhua Cao,Chenglong Li,Bin Zhao,Zhili Ma,Jingrong Zhou,Yunping Hu,Xiao Zhang,Yi Yang,Guangjie Duan,Xiu-wu Bian,Gan Tian
Radiotherapy (RT) is one of the important clinical treatments for local control of triple-negative breast cancer (TNBC), but radioresistance still exists. Ferroptosis has been recognized as a natural barrier for cancer progression and represents a significant role of RT-mediated anticancer effects, while the simultaneous activation of ferroptosis defensive system during RT limits the synergistic effect between RT and ferroptosis. Herein, we engineered a tumor microenvironment (TME) degradable nanohybrid with a dual radiosensitization manner to combine ferroptosis induction and high-Z effect based on metal–organic frameworks for ferroptosis-augmented RT of TNBC. The encapsulated l-buthionine-sulfoximine (BSO) could inhibit glutathione (GSH) biosynthesis for glutathione peroxidase 4 (GPX4) inactivation to break down the ferroptosis defensive system, and the delivered ferrous ions could act as a powerful ferroptosis executor via triggering the Fenton reaction; the combination of them induces potent ferroptosis, which could synergize with the surface decorated Gold (Au) NPs-mediated radiosensitization to improve RT efficacy. In vivo antitumor results revealed that the nanohybrid could significantly improve the therapeutic efficacy and antimetastasis efficiency based on the combinational mechanism between ferroptosis and RT. This work thus demonstrated that combining RT with efficient ferroptosis induction through nanotechnology was a feasible and promising strategy for TNBC treatment.
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ACS Nano
·
2023
·
IF 17.1
Ke Li,Kun Xu,Ye He,Yulu Yang,Meijun Tan,Yulan Mao,Yanan Zou,Qian Feng,Zhong Luo,Kaiyong Cai
The hypoxia microenvironment of solid tumors poses a technological bottleneck for ferroptosis and immunotherapy in clinical oncology. Nanoreactors based on special physiological signals in tumor cells are able to avoid various tumor tolerance mechanisms by alleviating the intracellular hypoxia environment. Herein we reported a nanoreactor Cu2–xSe that enabled the conversion of Cu elements between Cu+ and Cu2+ for the generation of O2 and the consumption of intracellular GSH content. Furthermore, to enhance the catalytic and ferroptosis-inducing activities of the nanoreactors, the ferroptosis agonist Erastin was loaded on the ZIF-8 coating on the surface of Cu2–xSe to up-regulate the expression of NOX4 protein, increase the intracellular H2O2 content, catalyze the Cu+ to produce O2 and activate ferroptosis. In addition, the nanoreactors were simultaneously surface functionalized with PEG polymer and folic acid molecules, which ensured the in vivo blood circulation and tumor-specific uptake. In vitro and in vivo experiments demonstrated that the functionalized self-supplying nanoreactors can amplify the ability to generate O2 and consume intracellular GSH via the interconversion of Cu elements Cu+ and Cu2+, and impair the GPX4/GSH pathway and HIF-1α protein expression. At the same time, by alleviating the intracellular hypoxia environment, the expression of miR301, a gene in the secreted exosomes was decreased, which ultimately affected the phenotype polarization of TAMs and increased the content of IFN γ secreted by CD8+ T cells, which further promoted the ferroptosis induced by Erastin-loaded nanoreactors. This combined therapeutic strategy of activating the tumor immune response and ferroptosis via self-supplying nanoreactors provides a potential strategy for clinical application.
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CHEMISTRY OF MATERIALS
·
2023
·
IF 8.6
Xingyu Fan,Botao Chen,Hui Xu,Anqiang Pan,Shuquan Liang,Songwen Tan,Yongju He
Depleting intracellular glutathione (GSH) has emerged as a potent strategy to combat cancer. However, the existing GSH-depleting agents are too toxic or ineffective and standalone GSH depletion fails to yield a satisfactory curative effect. Herein, we present an intelligent nanoparticle that possesses GSH depletion, glucose consumption accompanied with H2O2 production, and NO generation properties for multimodal cancer therapy. The nanoparticle is constructed by synthesis of tetrasulfide bond-doped mesoporous silica nanoparticles followed by conjugating glucose oxidase (GOx) on the surface and loading l-arginine (l-Arg) into the mesopores. In this nanoparticle, the doped tetrasulfide bonds can quickly deplete GSH, which increases the cellular reactive oxygen species concentration to induce ferroptosis and meanwhile triggers particle biodegradation to expose the loaded l-Arg. Moreover, the elevated H2O2 level activates l-Arg to release NO for NO therapy. GOx consumes glucose to initiate starvation therapy and simultaneously produces a large amount of H2O2. Importantly, the produced H2O2 can not only potentiate ferroptosis but also promote NO release to enhance NO therapy. Besides, NO could in turn improve the efficacy of starvation therapy by damaging the mitochondria to block energy supply. In vitro and in vivo studies demonstrate that the nanoparticles show a great synergistic effect of ferroptosis/starvation/NO therapy, which can significantly kill cancer cells and remarkably inhibit tumor growth without obvious side effects. Therefore, we think that the designed nanoparticles may provide a promising paradigm for synergistic cancer therapy and hold a prospect in clinical trials.
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Molecular Medicine Reports
·
2023
·Vol. 27
·期 2
·1-11
·
IF 3.4
Jing Zhao,Mingming Ma,Lei Li,Gaoli Fang
Oxysophoridine (OSR) is an alkaloid extracted from Sophora alopecuroides L. and exerts beneficial effects in cerebral ischemia/reperfusion (I/R) injury. However, the molecular mechanism underlying the regulatory effects of OSR in cerebral I/R injury remains unclear. In the present study, a cerebral I/R injury rat model was established by occlusion of the right middle cerebral artery. Hematoxylin and eosin and triphenyltetrazolium chloride staining were performed to assess histopathological changes and the extent of cerebral injury to the brain. A Cell Counting Kit‑8 and TUNEL assay and western blotting were performed to assess cell viability and apoptosis. Ferroptosis and oxidative stress were evaluated based on ATP and Fe2+ levels and DCFH‑DA staining. The protein expression levels of inflammatory factors were assessed using ELISA. The protein expression levels of members of the toll‑like receptor (TLR)4/p38MAPK signaling pathway were evaluated using immunofluorescence staining and western blotting. The results demonstrated that OSR decreased brain injury and neuronal apoptosis in the hippocampus in I/R‑induced rats. OSR inhibited reactive oxygen species (ROS) production, decreased levels of ATP, Fe2+ and acyl‑CoA synthetase long‑chain family member 4 (ACSL4) and transferrin 1 protein and increased the protein expression levels of ferritin 1 and glutathione peroxidase 4. Furthermore, OSR blocked TLR4/p38MAPK signaling in brain tissue in the I/R‑induced rat. In vitro experiments demonstrated that TLR4 overexpression induced generation of ROS, ATP and Fe2+, which promoted the expression of ferroptosis‑associated proteins in hippocampal HT22 neuronal cells. The ferroptosis inducer erastin decreased the effects of OSR on oxygen‑glucose deprivation/reoxygenation (OGD/R)‑induced cell viability, oxidative stress and inflammatory response. Together, the results demonstrated that OSR alleviated cerebral I/R injury via inhibition of TLR4/p38MAPK‑mediated ferroptosis.
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ACS Nano
·
2018
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IF 13.709
Shuaifei Wang,Fangyuan Li,Ruirui Qiao,Xi Hu,Hongwei Liao,Lumin Chen,Jiahe Wu,Haibin Wu,Meng Zhao,Jianan Liu,Rui Chen,Xibo Ma,Dokyoon Kim,Jihong Sun,Thomas P. Davis,Chunying Chen,Jie Tian,Taeghwan Hyeon,Daishun Ling
Ferroptosis, an iron-based cell-death pathway, has recently attracted great attention owing to its effectiveness in killing cancer cells. Previous investigations focused on the development of iron-based nanomaterials to induce ferroptosis in cancer cells by the up-regulation of reactive oxygen species (ROS) generated by the well-known Fenton reaction. Herein, we report a ferroptosis-inducing agent based on arginine-rich manganese silicate nanobubbles (AMSNs) that possess highly efficient glutathione (GSH) depletion ability and thereby induce ferroptosis by the inactivation of glutathione-dependent peroxidases 4 (GPX4). The AMSNs were synthesized via a one-pot reaction with arginine (Arg) as the surface ligand for tumor homing. Subsequently, a significant tumor suppression effect can be achieved by GSH depletion-induced ferroptosis. Moreover, the degradation of AMSNs during the GSH depletion contributed to T1-weighted magnetic resonance imaging (MRI) enhancement as well as on-demand chemotherapeutic drug release for synergistic cancer therapy. We anticipate that the GSH-depletion-induced ferroptosis strategy by using manganese-based nanomaterials would provide insights in designing nanomedicines for tumor-targeted theranostics.
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INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
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2025
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IF 8.5
Juan Wang,Junyu Wang,Jun Zhang,Haoran Ye,Dawei Wang,Ling Tao,Yongchao Yao,Ying Chen,Xiangchun Shen
As a notoriously incurable tumor, triple-negative breast cancer (TNBC) exhibits significant sensitivity to ferroptosis and the glutathione (GSH) antioxidant defense system plays a crucial role in its progression. Herein, we report a bimetallic chitosan/hyaluronic acid nanoparticle (5FCN, with a Fe/Cu mass ratio of 5:5) that employs a self-amplified dual mechanism of ferroptosis and cuproptosis for TNBC therapy. Hyaluronic acid in 5FCN specifically binds to the overexpressed CD44 receptor on TNBC cells. This allows 5FCN to enter cells via receptor-mediated endocytosis, then release metal ions in acidic environments. Released Fe 3+ and Cu 2+ react with GSH in tumor cells, weakening the antioxidant system and producing Fe 2+ and Cu + . These ions trigger Fenton/Fenton-like reactions with H 2 O 2 , generating toxic hydroxyl radicals (·OH) to boost ferroptosis. Meanwhile, high-valent Cu 2+ and Fe 3+ are produced, forming a cycle for GSH depletion and ·OH generation. As H 2 O 2 depletes, the rising Cu + level in cells causes lipoylated protein aggregation, amplifying cuproptosis. In vitro and in vivo studies demonstrated that 5FCN exhibited superior cell-killing efficacy against TNBC with few side effects. Collectively, 5FCN represents a potential drug to self-amplify ferroptosis/cuproptosis in TNBC.
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Heliyon
·
2024
·
IF 3.4
Guo-qiang Liang,Wei Mu,Chun-bo Jiang
Evidence indicates that Baicalein can ameliorate renal interstitial fibrosis by inducing myofibroblast apoptosis and inhibit the RLS3-induced ferroptosis in melanocytes. However, the relationship between renal interstitial fibrosis and anti-ferroptosis affected by Baicalein remains unclear. In our study, the anti-fibrosis and anti-ferroptosis effects of Baicalein were assessed in a rat model induced by the UUO method in vivo , and the effects of Baicalein on Erastin-induced ferroptosis of renal MPC-5 cells were examined by Western blot of fibrosis-related and ferroptosis-related proteins in vitro . In the UUO-induced rat model, Baicalein decreased kidney weight loss, improved renal function assessed the biomarks of urinary albumin excretion, serum creatine, and BUN levels, and reduced renal tubular injury. Furthermore, Baicalein inhibited renal ferroptosis by reducing ROS and MDA levels and increasing SOD and GSH levels in the UUO rat model. In addition, Baicalein potently reduced the expression of fibrosis-related proteins such as TGF-β1, a-SMA, and Smad-2 to prevent renal interstitial fibrosis, and increased the expression of ferroptosis-related proteins such as SLC7A11, GPX4, and FTH to inhibit ferroptosis both in vitro and in vivo . Taken together, Baicalein exerts anti-fibrosis activity by reducing the ferroptosis response on the UUO-induced rat model and renal MPC5 cells. Therefore, Baicalein, as a novel therapeutic method on kidney diseases with strong activity in suppressing ferroptosis, could be a potential alternative treatment for renal interstitial fibrosis.
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ChemNanoMat
·
2024
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IF 2.6
Yajun Ma,Jianquan Chen,Yan Yang,Hanqing Qian
Lactate accumulated in Tumor is a key oncometabolite and associated with various oncogenic processes, including proliferation, invasion, angiogenesis, metastasis, immunosuppression and therapeutic resistance. Particularly, lactate contributes to the apoptosis and ferroptosis resistance in cancer cells. Consequently, blockade of lactate provides a promising opportunity for cancer therapy. However, due to abnormal tumor microenvironment (TME) and intracellular glutathione (GSH) mediated ferroptosis resistance, the current approaches for regulating lactate to sensitize cells to apoptosis and ferroptosis are still challenging. Herein, we developed a catalytic lactate oxidizing liposomes (Lip-LM) incorporated with lactate oxidase (LOX)-loaded MnO2 nanoparticles. O2 regenerated from H2O2 constitute closed-loop of lactate oxidation catalyzed by LOX, enhancing the lactate-consuming efficacy in TME. Besides, glutathione is consumed by MnO2 to amplify the ferroptosis susceptibility of cancer cells. The results showed that Lip-LM achieved synergistical apoptosis and ferroptosis to enhance the anti-tumor efficacy of amplified oxidative stress in cancer cells through the strategy of self-sufficient O2 supplying and GSH consumption. The results of transcriptomics and proteomics analyses also support the synergistical anti-tumor mechanisms of Lip-LM. Hence, it is a promising catalytic nanoplatform combined lactate regulation and oxidative stress amplification and have great potential to further enhance therapeutic outcomes based on synergistical apoptosis and ferroptosis.
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ACS Applied Materials & Interfaces
·
2025
·
IF 8.2
Yandai Lin,Xinru Kong,Zhe Liu
Nitric oxide (NO)-based gas therapy has attracted increasing attention as a promising approach for tumor treatment, but elevated levels of glutathione (GSH) in the tumor microenvironment significantly limit their therapeutic effectiveness. In this study, a type of engineered photoactivatable nanomicelles Ce6/NI@PEP@HA (CNPH) were developed for combinational photodynamic and NO gas therapy. CNPH was capable of targeted accumulation to tumors, where it depleted GSH and released NO to effectively produce reactive oxygen species (ROS) with oxidative damage under laser irradiation at 660 nm. The GSH consumption induced the deactivation of glutathione peroxidase activity, leading to enhanced accumulation of toxic lipid peroxide and enabled a ferroptosis-like therapeutic outcome. Additionally, the effective production of NO and ROS resulted in mitochondrial dysfunction, characterized by the disruption of mitochondrial membrane potential and decreased adenosine triphosphate concentration. The in vivo animal experiments indicated that the combinational photodynamic and NO gas therapy achieved a tumor inhibition of 89.1%, and it has proven to be a more effective tumor therapy strategy in contrast to any single modality. In consequence, ferroptosis-like combinational tumor therapy has opened up a new horizon to a cutting-edge and noninvasive paradigm for advanced tumor treatments.
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