Nutrients
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2023
·Vol. 15
·期 5
·1090
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IF 5.9
Yunpeng Zhang,Shuang Liu,Jing Peng,Shifeng Cheng,Qingling Zhang,Nan Zhang,Zandong Zhou,Yue Zhang,Yang Zhao,Tong Liu
Mitochondria-dependent ferroptosis plays an important role in the pathogenesis of doxorubicin (DOX)-induced cardiotoxicity (DIC), which remains a clinical challenge due to the lack of effective interventions. Cerium oxide (CeO2), a representative nanozyme, has attracted much attention because of its antioxidant properties. This study evaluated CeO2-based nanozymes for the prevention and treatment of DIC in vitro and in vivo by adding nanoparticles (NPs), which were synthesized by biomineralization, to the culture or giving them to the mice, and the ferroptosis-specific inhibitor ferrostatin-1 (Fer-1) was used as control. The prepared NPs exhibited an excellent antioxidant response and glutathione peroxidase 4 (GPX4)-depended bioregulation, with the additional merits of bio-clearance and long retention in the heart. The experiments showed that NP treatment could significantly reverse myocardial structural and electrical remodeling, and reduce myocardial necrosis. These cardioprotective therapeutic effects were associated with their ability to alleviate oxidative stress, mitochondrial lipid peroxidation, and mitochondrial membrane potential damage, with a superior efficiency to the Fer-1. The study also found that the NPs significantly restored the expression of GPX4 and mitochondrial-associated proteins, thereby restoring mitochondria-dependent ferroptosis. Therefore, the study provides some insights into the role of ferroptosis in DIC. It also shows that CeO2-based nanozymes could be a promising prevention and treatment candidate as a novel cardiomyocyte ferroptosis protector to mitigate DIC and improve prognosis and quality of life in cancer patients.Keywords:doxorubicin-induced cardiomyopathy;ferroptosis;mitochondria;nanozyme;oxidative stress;biomineralization
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Small
·
2025
·
IF 12.1
Jiajie Chen,Yitong Wang,Zhibo Yang,Kai Tang,Xinchun Liu,Hongshi Ma,Huamao Ye,Chengtie Wu,Yufang Zhu
Emerging evidence demonstrates that inducing ferroptosis, a nonapoptotic programmed cell death mode, holds significant potential for tumor treatment. However, current ferroptosis strategies utilizing exogenous Fenton-type heavy metal species or introducing glutathione (GSH)/glutathione peroxidase 4 (GPX4) suppressants are hampered by latent adverse effects toward organisms, while utilizing endogenous iron may cause undesirable tumor angiogenesis through specific signaling pathways. Here, a ferric ion (Fe 3+ )-responsive and DNAzyme-delivered coordination nanosystem (ZDD) is developed to achieve a novel scheme of synergistic tumor-specific ferroptosis and gene therapy, which modulates and harnesses the endogenous iron in tumors for inducing ferroptosis while intercepting tumor angiogenesis to enhance therapeutic efficacy. Profiting from the characteristic coordination structure and components, ZDD can not only specifically capture tumor endogenous Fe 3+ into the tumor cells to promote the catalytic generation of hydroxyl radicals (·OH) and superoxide anions (O 2 · − ) under acidic environment and the catalytic GSH oxidation, arousing potent ferroptotic cell death, but also effectively deliver specific DNAzyme and release abundant zinc ion (Zn 2+ ) as a powerful cofactor to activate the biocatalytic cleavage of vascular endothelial growth factor receptor 2 (VEGFR2) gene for angiogenesis suppression. Ultimately, the ZDD-enabled synergistic therapy prominently inhibited tumor growth and prevented metastasis, representing a promising nanotherapeutic formula for safe and efficient tumor therapy.
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CHEMICAL ENGINEERING JOURNAL
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2024
·
IF 13.3
Yixun Jin,Jia Huang,Yuming Tang,Zengyue Li,Amin Zhang,Ziyun Yang,Jiani Song,Xinyang Huang,Yaya Bai,Chao Sun,Xuejiao Wu,Jin Cheng,Lifu Wang,Qian Zhang,Weiyan Yao
Metal-doped iron oxide nanoparticles have attracted increasing attention for their Fenton reaction ability, which converts H 2 O 2 to cytotoxic reactive oxygen species (ROS) and is recently utilized as ferroptosis activator in pancreatic cancer therapy. However, low intracellular H 2 O 2 level hinders ferroptosis effect and leads to unsatisfactory efficacy. Herein, a transferrin coated and tumor homing peptide decorated bimetallic magnetic nanoparticles copper-doped iron oxide nanosystems embedded with photothermal agent IR820 and iron ions (denoted as PCTIFL) is constructed for synergistic treatment for pancreatic cancer by combining ferroptosis and photothermal/photodynamic therapy (PTT/PDT) under 808 nm laser irradiation. Benefiting from the homologous targeting property of LyP-1, the nanosystems can be precisely delivered and gradually accumulate at tumor site. For the synergistic therapy, IR820 generates ROS via photodynamic effect and enables cancer cell temperature elevation via PTT effect upon 808 nm laser irradiation on the one hand and metal ions such as Fe 2+ , Fe 3+ and Cu 2+ catalyze H 2 O 2 into ROS and finally triggered ferroptosis on the other hand. Moreover, PCTIFL nanosystems can be applied in pancreatic cancer diagnosis for their MRI/NIR dual imaging function. Overall, this work not only presents a promising strategy for augmenting the ferroptosis induced by iron oxide, but also a fantastic paradigm for pancreatic cancer diagnosis and synergistic therapy.
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Asian Journal of Pharmaceutical Sciences
·
2025
·
IF 11.9
Wei-Ran Cao,Xue Zhang,Jia-Xuan Chen,Lu Sun,Hui-Ning He,Fei Yu
Mitochondria provides adenosine triphosphate for multiple vital movements to ensure tumor cell proliferation. Compared to the broadly used method of inducing DNA replication arrest to kill cancer, inducing mitochondria damage to cause energy shortage is quite promising as it can inhibit tumor cell bioactivities, increase intracellular accumulation of toxic drugs, eventually sensitize chemotherapy and even reverse drug resistance. Breaking the balance of glutathione (GSH) and reactive oxygen species (ROS) contents have been proven efficient in destroying mitochondria respectively. Herein, apigenin, a GSH efflux reagent, and 2′-deoxy-5-fluorouridine 5′-monophosphate sodium salt (FdUMP) that could induce toxic ROS were co-delivered by constructed lipid nanoparticles, noted as Lip@AF. An immune-checkpoint inhibition reagent CD276 antibody was modified onto the surface of Lip@AF with high reaction specificity (noted as αCD276-Lip@AF) to enhance the recognition of immune cells to tumor. Results showed that the redox balance was destroyed, leading to severe injury to mitochondria and cell membrane. Furthermore, synergistic DNA/RNA replication inhibition caused by inhibiting the function of thymidylate synthase were observed. Eventually, significantly enhanced cytotoxicity was achieved by combining multiple mechanisms including ferroptosis, apoptosis and pyroptosis. In vivo , strengthen tumor growth inhibition was achieved by αCD276-Lip@AF with high biosafety, providing new sights in enhancing chemotherapy sensitiveness and achieving high-performance chemo-immunotherapy.
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Advanced Science
·
2026
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IF 14.1
Baixi Chen,Ziduan Ding,Ruomei Li,Cheng Zhu,Zhiyu Zhu,Zitong Yang,Luyao Qu,Jin Hao,Lunguo Xia,Bing Fang,Lu Liu
Senescent bone repair remains a formidable clinical challenge without an entirely satisfactory strategy. Emerging evidence has identified macrophage senescence as a critical determinant of impaired bone healing in the aged skeleton, and precisely reversing macrophage senescence has therefore emerged as a highly promising therapeutic approach. In this study, guided by multi‐omics features of senescent macrophages, we develop lithium‐doped hydroxyapatite nanowires (Li‐nHAP) and demonstrate that Li‐nHAP effectively alleviates macrophage senescence and subsequently enhances the osteogenic differentiation of aged bone marrow mesenchymal stem cells. Mechanistically, we identify the lysosome‐dependent ferroptosis axis as a previously unrecognized target mediating the anti‐senescent effects of Li‐nHAP in bone marrow‐derived macrophages. Specifically, Li‐nHAP re‐establishes lysosomal homeostasis, including restoring acidity, preserving membrane integrity, maintaining iron storage, and enhancing hydrolytic activity, thereby suppressing ferroptosis and ultimately reversing macrophage senescence. In vivo studies further validate that Li‐nHAP significantly alleviates macrophage ferroptosis and senescence, reduces local iron accumulation, and accelerates bone regeneration in an aged mandibular defect model. Collectively, these findings establish Li‐nHAP as a novel osteo‐immunomodulatory biomaterial that offers a promising strategy for the repair of age‐related bone defects. Li‐nHAP+GelMA promotes mandibular bone regeneration in aged mice by remodeling the senescent immune microenvironment. Local delivery of Li‐nHAP restores lysosomal homeostasis in senescent macrophages, reduces intracellular labile Fe 2 + accumulation, ROS production, and lipid peroxidation, thereby suppressing macrophage ferroptosis and senescence‐associated SASP signaling. This macrophage rejuvenation alleviates the aged inflammatory microenvironment and enhances osteogenesis, ultimately improving bone repair in mandibular defects.
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JOURNAL OF ETHNOPHARMACOLOGY
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2024
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IF 4.8
Liangliang Kong,Yan Liu,Jingwei Li,Yanyan Wang,Pengmin Ji,Qifeng Shi,Min Han,Hanyang Xu,Weiping Li,Weizu Li
Ethnopharmacological relevance Ginseng is a valuable herb in traditional Chinese medicine. Modern research has shown that it has various benefits, including tonifying vital energy, nourishing and strengthening the body, calming the mind, improving cognitive function, regulating fluids, and returning blood pressure, etc. Rg1 is a primary active component of ginseng. It protects hippocampal neurons, improves synaptic plasticity, enhances cognitive function, and boosts immunity. Furthermore, it exhibits anti-aging and anti-fatigue properties and holds great potential for preventing and managing neurodegenerative diseases (NDDs). Aim of the study The objective of this study was to examine the role of Rg1 in treating chronic inflammatory NDDs and its molecular mechanisms. Materials and methods In vivo , we investigated the protective effects of Rg1 against chronic neuroinflammation and cognitive deficits in mice induced by 200 μg/kg lipopolysaccharide (LPS) for 21 days using behavioral tests, pathological sections, Western blot, qPCR and immunostaining. In vitro experiments involved the stimulation of HT22 cells with 10 μg/ml of LPS, verification of the therapeutic effect of Rg1, and elucidation of its potential mechanism of action using H2DCFDA staining, BODIPY™ 581/591 C11, JC-1 staining, Western blot, and immunostaining. Results Firstly, it was found that Rg1 significantly improved chronic LPS-induced behavioral and cognitive dysfunction in mice. Further studies showed that Rg1 significantly attenuated LPS-induced neuronal damage by reducing levels of IL-6, IL-1β and ROS, and inhibiting AIM2 inflammasome. Furthermore, chronic LPS exposure induced the onset of neuronal ferroptosis by increasing the lipid peroxidation product MDA and regulating the ferroptosis-associated proteins Gpx4, xCT, FSP1, DMT1 and TfR, which were reversed by Rg1 treatment. Additionally, Rg1 was found to activate Nrf2 and its downstream antioxidant enzymes, such as HO1 and NQO1, both in vivo and in vitro . In vitro studies also showed that the Nrf2 inhibitor ML385 could inhibit the anti-inflammatory, antioxidant, and anti-ferroptosis effects of Rg1. Conclusions This study demonstrated that Rg1 administration ameliorated chronic LPS-induced cognitive deficits and neuronal ferroptosis in mice by inhibiting neuroinflammation and oxidative stress. The underlying mechanisms may be related to the inhibition of AIM2 inflammasome and activation of Nrf2 signaling. These findings provide valuable insights into the treatment of chronic neuroinflammation and associated NDDs.
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JOURNAL OF MEDICINAL CHEMISTRY
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2024
·
IF 6.8
Lie-Feng Ma,Li−Li Xu,Ling-Jie Yuan,Xi Yang,Rui Wu,Shu-Min Bao,Yi-Li Chen,Hong-Liang Duan,Luo Fang,Hua-Jun Zhao,Zha-Jun Zhan
Triple-negative breast cancer (TNBC) is a highly lethal malignancy, and its clinical management encounters severe challenges due to its high metastatic propensity and the absence of effective therapeutic targets. To improve druggability of aurovertin B (AVB), a natural polyketide with a significant antiproliferative effect on TNBC, a series of NO donor/AVB hybrids were synthesized and tested for bioactivities. Among them, compound 4d significantly inhibited the proliferation and metastasis of TNBC in vitro and in vivo with better safety than that of AVB. The structure−activity relationship analysis suggested that the types of NO donor and the linkers had considerable effects on the activities. Mechanistic investigations unveiled that 4d induced apoptosis and ferroptosis by the reduction of mitochondrial membrane potential and the down-regulation of GPX4, respectively. The antimetastatic effect of 4d was associated with the upregulation of DUSP1. Overall, these compelling results underscore the tremendous potential of 4d for treating TNBC.
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EUROPEAN JOURNAL OF PHARMACOLOGY
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2024
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IF 4.2
Maoshan Wang,Yingxue Liu,Houda Gui,Gaoqiang Ma,Binyang Li,Zhanwei Zhang,Gyeonghwi Yu,Ailin Wu,Xin Xu,Dongjiao Zhang
Eldecalcitol (ED-71), a novel active form of vitamin D, shows potential in treating osteoporosis. However, its underlying mechanisms of action remain to be determined. This study aimed to investigate the effect of ED-71 on bone regeneration and to illustrate its mode of action. The in-vitro model was developed using rat primary osteoblasts cultured under high-glucose conditions, and these cells were treated with ED-71. Additionally, an in vivo model of cranial bone defects was established in type 2 diabetic rats, and ED-71 was administered by gavage. The results demonstrated that ED-71 prevented osteoblast cell death, enhanced rat primary osteoblasts' osteogenic capacity, and attenuated the overexpression of hypoxia-inducible factor 1α (HIF1α) induced by high glucose levels. Furthermore, ED-71 increased glutathione peroxidase 4 (GPX4) levels and inhibited ferroptosis in response to hyperglycemic stimulation. Notably, interference with the HIF1α activator and ferroptosis activator Erastin significantly reduced the therapeutic effects of edetate osteolysis. These findings were further tested in vivo experiments. These results suggest that ED-71 activates the HIF1α pathway in vivo and in vitro, effectively relieving the ferroptosis induced by high glucose. Significantly, ED-71 may improve osteogenic disorders caused by diabetes.
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Small
·
2024
·
IF 13
Can Yao,Rui Zhang,Zongliang Xie,Yundi Wu,Xilong Wu
Nanozymes mimicking enzymes show great promise in anti-tumor therapy but are often limited by their low catalytic activity and lack of tumor specificity in hostile tumor microenvironments. This study develops a novel nanozyme, D/P@ZUCO, utilizing metal–organic frameworks (MOFs) with glutathione oxidase, peroxidase, and catalase-like activities. D/P@ZUCO is synthesized using ZnFe 2 O 4 and NH 2 -UiO66 (Cu/Zr) through an in situ growth method, followed by loading with doxorubicin (DOX) and primaquine (PQ), and functionalization with oxidized hyaluronic acid (OHA). It efficiently catalyzes the conversion of hydrogen peroxide (H 2 O 2 ) into hydroxyl radicals (·OH) and glutathione (GSH) into glutathione disulfide (GSSH), initiating ferroptosis in cancer cells. Additionally, the conversion of excess H 2 O 2 into oxygen (O 2 ) enhances the apoptosis effects of DOX. Importantly, the inhibition of autophagy by D/P@ZUCO exacerbates ferroptosis and immunogenic cell death (ICD), triggering a potent anti-tumor immune response. The targeted drug delivery of D/P@ZUCO is facilitated by magnetic guidance and interactions between OHA and CD44 receptors. D/P@ZUCO demonstrates effective cancer treatment by triggering multiple cell death pathways through a synergistic combination of enzymatic actions, serving as a paradigm for systemic activation of multiple enzymes in triple-negative breast cancer therapy.
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ACS Applied Materials & Interfaces
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2024
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IF 8.3
Zhenxin Guan,Song Li,Yurong Liu,Xiaokang Zhang,Yunheng Liu,Fangying Zou,Shaojiao Liu,Xinhui Shan,Yu Duan,Li Ma,Jinghui Hu,Jing Chen
Ferroptosis is an iron-dependent cell death pathway triggered by the toxic accumulation of lipid peroxides on cellular membranes. However, an imbalance in iron metabolism in tumor cells leads to the insufficient accumulation of iron ions in the iron pool, which inhibits ferroptosis. Nonspecific delivery of iron species may increase the risk of promoting tumor proliferation as well as trigger undesirable detrimental effects such as anaphylactic reactions in normal tissues. This study found that a constructed self-enhancing targeted nanocarrier can accurately regulate the iron pool levels in tumor cells. We constructed a programmatic targeted enhanced nanotherapy strategy by loading the ferroptosis inducer erastin into a self-enhancing targeted nanocarrier. This nanosystem was more effective at inducing tumor ferroptosis after upregulating the iron pool levels in tumor cells with self-enhancing targeted nanocarriers. Both in vitro and in vivo outcomes demonstrated notable anticancer ferroptosis efficacy, indicating that self-enhancing targeted nanocarriers can effectively regulate the level of the iron pool in tumor cells and promote ferroptosis. The combination of this nanotherapy strategy with self-enhancing targeted chemotherapy nanomedicines can achieve complete tumor clearance. Moreover, this self-enhancing targeted ferroptosis nanotherapy strategy is expected to be beneficial for future progress in the field of cancer self-enhancing targeted therapy.
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Asian Journal of Pharmaceutical Sciences
·
2024
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IF 10.7
Ting Yang,Zihan Liu,Zixuan Fu,Xiaojie Zhang,Yongjin Cao,Qiangwei Liang,Jiale Miao,Hao Yang,Tong Zhang,Jing Hei,Weiqing Ni,Yanhua Liu
Ferroptosis can serve as a potent strategy for regulating cell death via lipid peroxidation and the imbalance of the antioxidant system resulting from iron accumulation in triple-negative breast cancer (TNBC) therapy. However, the ferroptosis accompanied with down-regulation of glutathione peroxidase 4 (GPX4) lead to CD36-mediated tumor-infiltrating CD8 + T cells uptaking fatty acids, resulting in the negative action on immunotherapeutic efficacy. Herein, the albumin nanoparticles, abbreviated as LHS NPs, were designed by co-assembly of hemin, linoleic acid-cystamine, and a CD36 inhibitor sulfosuccinimide oleate, to bi-directionally manipulated ferroptosis in tumor and CD8 + T cells for TNBC therapy. LHS NPs exerted more efficient reactive oxygen species generation, glutathione depletion and malondialdehyde production by the combinatory strategy of classical and non-classical ferroptosis modes, which amplified the positive action on ferroptosis in tumor cells. Meanwhile, LHS manipulated the negative action of ferroptosis by inhibiting the CD36 mediated-lipid peroxidation in CD8 + T cells, thereby activating the immunotherapeutic efficacy with the improvements on induction of immunogenic cell death, proliferation of CD4 + CD8 + T cells and natural killer cells, alleviation immunosuppressive regulatory T cells and myeloid-derived suppressor cells, and repolarization of the M2- to M1-phenotype tumor-associated macrophages. Thus, LHS NPs demonstrated an improved antitumor efficacy in suppressing the tumor growth and lung metastasis of 4T1-tumor mice. Our work gives novel insights for the bi-directionally manipulating ferroptosis in tumor and CD8 + T cells on TNBC chemoimmunotherapy.
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CARBOHYDRATE POLYMERS
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2024
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IF 10.7
Ning Wang,Qiyu Zhang,Zhuoya Wang,Yichao Liu,Sen Yang,Xuerong Zhao,Jinyong Peng
Triple-negative breast cancer (TNBC) poses a serious threat to women's life and health due to its high malignancy, strong invasiveness, and propensity for early recurrence and metastasis. Therefore, there is an urgent need to develop a highly effective and low-toxic TNBC treatment scheme to enhance the anti-cancer efficacy and prolong the survival of patients. In this work, we designed and synthesized a chemodynamic therapy (CDT) agent (HA-Fc-Mal). The chemo/chemodynamic (CT/CDT) nanoparticle (HCM@DOX) based on hyaluronic acid induces ferroptosis and apoptotic for TNBC therapy was constructed via self-assembled of HA-Fc-Mal and doxorubicin (DOX). HCM@DOX orderly realized the TNBC targeting, controlled DOX release, GSH depletion and induce ROS erupt. In vivo and in vitro experiments confirmed that HCM@DOX inhibited the growth of 4 T1 tumors through ferroptosis and apoptosis, and the tumor inhibition rate was as high as 81.87 %. In addition, HCM@DOX significantly inhibited lung metastasis and exhibited excellent biosafety. Overall, our findings offer a new strategy for TNBC therapy using a CT/CDT nanoparticle that induces ferroptosis and apoptosis.
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