Signal Transduction and Targeted Therapy
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2022
·Vol. 7
·期 1
·1-13
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IF 38.104
Ma Xiao-Hui,Liu Jiang-Han-Zi,Liu Chun-Yu,Sun Wan-Yang,Duan Wen-Jun,Wang Guan,Kurihara Hiroshi,He Rong-Rong,Li Yi-Fang,Chen Yang,Shang Hongcai
Myocardial ischemia/reperfusion (I/R) injury is a classic type of cardiovascular disease characterized by injury to cardiomyocytes leading to various forms of cell death. It is believed that irreversible myocardial damage resulted from I/R occurs due to oxidative stress evoked during the reperfusion phase. Here we demonstrate that ischemia triggers a specific redox reaction of polyunsaturated fatty acids (PUFA)-phospholipids in myocardial cells, which acts as a priming signaling that initiates the outbreak of robust oxidative damage in the reperfusion phase. Using animal and in vitro models, the crucial lipid species in I/R injury were identified to be oxidized PUFAs enriched phosphatidylethanolamines. Using multi-omics, arachidonic acid 15-lipoxygenase-1 (ALOX15) was identified as the primary mediator of ischemia-provoked phospholipid peroxidation, which was further confirmed using chemogenetic approaches. Collectively, our results reveal that ALOX15 induction in the ischemia phase acts as a “burning point” to ignite phospholipid oxidization into ferroptotic signals. This finding characterizes a novel molecular mechanism for myocardial ischemia injury and offers a potential therapeutic target for early intervention of I/R injury.
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Biomaterials Science
·
2021
·Vol. 9
·期 21
·7228-7236
·
IF 6.843
Wenjun Liu,Jieyuan Zhang,Liang Ding,Weifeng Ni,Junjie Yuan,Haijun Xiao,Jingwei Zhang
Photodynamic and ferroptosis therapies for cancer treatment are restricted by the scarcity of oxygen and Fe in cancer cells, and the complicated structure of delivery systems. Herein, a red blood cell-derived vehicle (RDV) inherently enriched with hemoglobin co-delivers a photosensitizer, Ce6, and a ferroptosis promoter, sorafenib (SRF) into cancer cells for boosting oxygen and providing iron, which leads to enhanced PDT and stronger ferroptosis therapy. Damage to the RDV membrane under local irradation leads to SRF release at the tumor site for tumor-targeted therapy. The lipid membrane of the RDV could also improve the drug delivery efficiency in vitro and in vivo. The novel nanosystem exhibited enhanced tumor killing efficacy and improved safety compared with traditional PDT and ferroptosis therapy.
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Applied Materials Today
·
2021
·
IF 10.041
Renting Jiang,Xin Li,Dun Hu,Min Zhu,Di Zhou,Mengying Yuan,Xin Hu,Shengdan Nie,Jiajia Liu,Haoyue Xiang,Hua Yang,Yi Zhang,Shan Wang
Upregulating the susceptibility of cancer cells to ferroptosis is crucial to upgrade anti-cancer efficiency of ferroptosis drug system. At present, optimizing the sensitizer for ferroptosis with expected mechanism and improved transport via facile nanocarriers still heavily rely on serendipitous discovery and repetitious assignment. Herein, we employ the tannic acid (TA)-templated silicon nanoparticle as nanocore to descend the lysosome-controlled disintegratable Fe 3+ @ [email protected] micelles (REFSM) to identify rapamycin as a ferroptosis sensitizer through autophagy-dependent/independent pathways. The as-prepared REFSM dissociates responding to the acidic condition and enzyme system of lysosomes, permitting Fe 3+ and erastin release to irritate ferroptosis, which is reinforced by released rapamycin via irritating ferritinophagy and lipophagy, and suppressing HIF-1α. The rapamycin-reinforced ferroptosis is demonstrated to be specific to H 2 O 2 -overloaded cancer cells. Moreover, the introduction of rapamycin reduces the positive charge of micelle and improves its distribution in tumors. Both the controllable dissociation and the improved charge of REFSM ensure its anti-cancer efficiency at trace amount of erastin (0.3 mg kg −1 ) and rapamycin (2.2 mg kg −1 ) and minimize the systematic toxicity. This archetypical template provides a versatile platform for rapamycin as sensitizer to enhance ferroptosis by displaying its multiple pharmacological mechanism, controlling its release and improving its distribution in vivo .
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Science Advances
·
2020
·Vol. 6
·期 18
·
IF 13.117
Chen-Cheng Xue,Meng-Huan Li,Yang Zhao,Jun Zhou,Yan Hu,Kai-Yong Cai,Yanli Zhao,Shu-Hong Yu,Zhong Luo
The rapid development of treatment resistance in tumors poses a technological bottleneck in clinical oncology. Ferroptosis is a form of regulated cell death with clinical translational potential, but the efficacy of ferroptosis-inducing agents is susceptible to many endogenous factors when administered alone, for which some cooperating mechanisms are urgently required. Here, we report an amorphous calcium carbonate (ACC)–based nanoassembly for tumor-targeted ferroptosis therapy, in which the totally degradable ACC substrate could synergize with the therapeutic interaction between doxorubicin (DOX) and Fe2+. The nanoplatform was simultaneously modified by dendrimers with metalloproteinase-2 (MMP-2)–sheddable PEG or targeting ligands, which offers the functional balance between circulation longevity and tumor-specific uptake. The therapeutic cargo could be released intracellularly in a self-regulated manner through acidity-triggered degradation of ACC, where DOX could amplify the ferroptosis effects of Fe2+ by producing H2O2. This nanoformulation has demonstrated potent ferroptosis efficacy and may offer clinical promise.
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FREE RADICAL BIOLOGY AND MEDICINE
·
2022
·
IF 8.101
Shanlong Zhang,Li Kang,Xiaoxue Dai,Junlan Chen,Zhengtao Chen,Meixiang Wang,Huantong Jiang,Xin Wang,Suqin Bu,Xinyuan Liu,Guohui Zhang,Hua Tang
Ferroptosis is a novel form of regulated cell death characterized by the iron-dependent accumulation of lipid peroxides to lethal levels, which is morphologically, biochemically, and genetically distinct from apoptosis, necroptosis, autophagy, and pyroptosis. Manganese play an important role in innate immunity and antitumor immunity. Many manganese-based nanomaterials induce tumor cell death by catalyzing the production of reactive oxygen species (ROS) within the tumor. However, the exact underlying mechanisms remain unclear. As research on ferroptosis advances and its regulatory mechanisms in tumors continue to be refined, more evidence has suggested that triggering ferroptosis in tumor cells is an effective strategy for tumor treatment. In this study, we found that administration of MnCl 2 to tumor cells resulted in lipid peroxidation and increased the levels of mitochondrial ROS, consequently leading to ferroptosis. Dihydroorotate dehydrogenase (DHODH)-mediated ferroptosis defence is a targetable vulnerability in cancer. We show that MnCl 2 downregulated DHODH expression in tumor cells, resulting in increased mitochondrial ROS and lipid peroxidation to induce ferroptosis. In addition, MnCl 2 enhanced the phosphorylation levels of STING, TBK1, and IRF3 and upregulated the expression of type-I interferon (IFN), produced by the cGAS–STING signaling pathway. When inhibiting the cGAS–STING signaling pathway or type-I IFN, DHODH expression was restored, reversing lipid peroxidation and ROS production and rescuing MnCl 2 -induced ferroptosis.. Knockout of IFNAR1 or overexpression of DHODH weakens the antitumor effect of MnCl 2 . Mechanistically, these results revealed that Manganese treatment-activated cGAS–STING signaling promote mitochondrial lipid peroxidation and ROS production by releasing type-I IFNs that reduce DHODH function and thereby inducing ferroptosis in tumor cells. This may provide a new strategy to complement existing antitumor treatment regimens.
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Redox Biology
·
2022
·
IF 10.787
Yi Zhao,Hao Zhang,Jia-Gen Cui,Jia-Xin Wang,Ming-Shan Chen,Hao-Ran Wang,Xue-Nan Li,Jin-Long Li
The global rate of human male infertility is rising at an alarming rate owing to environmental and lifestyle changes. Phthalates are the most hazardous chemical additives in plastics and have an apparently negative impact on the function of male reproductive system. Ferroptosis is a recently described form of iron-dependent cell death and has been linked to several diseases. Transferrin receptor (TfRC), a specific ferroptosis marker, is a universal iron importer for all cells using extracellular transferrin. We aim to investigate the potential involvement of ferroptosis during male reproductive toxicity, and provide means for drawing conclusions on the effect of ferroptosis in phthalates-induced male reproductive disease. In this study, we found that di (2-ethylhexyl) phthalate (DEHP) triggered blood-testis barrier (BTB) dysfunction in the mouse testicular tissues. DEHP also induced mitochondrial morphological changes and lipid peroxidation, which are manifestations of ferroptosis. As the primary metabolite of DEHP, mono-2-ethylhexyl phthalate (MEHP) induced ferroptosis by inhibiting glutathione defense network and increasing lipid peroxidation. TfRC knockdown blocked MEHP-induced ferroptosis by decreasing mitochondrial and intracellular levels of Fe 2+ . Our findings indicate that TfRC can regulate Sertoli cell ferroptosis and therefore is a novel therapeutic molecule for reproductive disorders in male patients with infertility.
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EUROPEAN JOURNAL OF PHARMACOLOGY
·
2026
·
IF 5.7
Meng Wang,Che Wang,Zhihao Liu,Xiaoyu Du,Lu Tian,Qi Li,Feng Zhang,Yingxiang Chen,Chengzhi Lu
Acteoside attenuates doxorubicin-induced cardiotoxicity and ferroptosis. • Acteoside preserves mitochondrial function in doxorubicin-exposed cardiomyocytes. • Acteoside promotes KEAP1 degradation and activates NRF2 signaling. • NRF2 inhibition attenuates the cardioprotective and anti-ferroptotic effects of ACT. : Doxorubicin (DOX)-induced cardiotoxicity (DIC) is a major limitation to the clinical use of DOX, highlighting the need for effective cardioprotective strategies. Although acteoside (ACT), a natural compound with antioxidant properties, has shown potential cardioprotective effects, its role in DIC, particularly in the regulation of ferroptosis, remains unclear. This study therefore investigated the protective effects of ACT against DIC and the underlying molecular mechanisms. Using C57BL/6 mice in vivo and H9c2 cells in vitro, we evaluated cardiac function, myocardial injury and histopathological alterations, ferroptosis-related changes, and key regulatory proteins. ACT significantly attenuated DOX-induced cardiac dysfunction, myocardial injury, and fibrosis. These protective effects were accompanied by suppression of ferroptosis, as evidenced by reduced iron accumulation and lipid peroxidation and restored expression of glutathione peroxidase 4 (GPX4) and the cystine/glutamate transporter (xCT). ACT also preserved mitochondrial membrane potential and reduced mitochondrial reactive oxygen species (ROS) levels, thereby alleviating mitochondrial dysfunction. Mechanistically, ACT may interact with Kelch-like ECH-associated protein 1 (KEAP1) and promoted KEAP1 degradation, thereby facilitating the nuclear translocation of nuclear factor erythroid 2-related factor 2 (NRF2) and increasing the expression of downstream antioxidant proteins, including heme oxygenase-1 (HO-1). Moreover, the NRF2 inhibitor ML385 significantly attenuated the protective effects of ACT, supporting the involvement of NRF2 signaling in ACT-mediated cardioprotection. Collectively, these findings suggest that ACT protects against DIC, at least in part, by promoting KEAP1 degradation, activating NRF2 signaling, and suppressing ferroptosis. This figure summarizes the mechanism by which ACT alleviates DOX-induced cardiotoxicity through the suppression of ferroptosis. ACT promotes KEAP1 degradation, reduces KEAP1-mediated NRF2 degradation, and enhances NRF2 nuclear translocation and downstream antioxidant and anti-ferroptotic signaling. These effects upregulate HO-1, xCT, and GPX4, reduce lipid ROS accumulation, improve mitochondrial function, and suppress cardiomyocyte ferroptosis. Collectively, the cardioprotective effects of ACT are mediated, at least in part, through activation of the KEAP1/NRF2 axis. Download: Download high-res image (175KB) Download: Download full-size image
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ENVIRONMENTAL TOXICOLOGY
·
2023
·
IF 4.5
Xia Wang,Dinggang Li,Xiangqin Zheng,Yifan Hong,Jie Zhao,Wei Deng,Mingxin Wang,Lianju Shen,Chunlan Long,Guanghui Wei,Shengde Wu
Di-(2-ethylhexyl) phthalate (DEHP), a widely used plasticizer, has been shown to cause reproductive toxicity, but the precise mechanism remains unclear. This study aimed to investigate the possible molecular mechanism of DEHP-induced testicular damage. In vivo study, we administered different doses of DEHP (0, 250, and 500 mg/kg/day) to male C57BL/6 mice from 22 and 35 days after birth. We found that DEHP exposure induced histopathological alterations in prepubertal testes, and testicular lipidomics indicated notable alterations in lipid metabolism and significant enrichment of ferroptosis. Further tests showed that ferrous iron (Fe 2+ ) and malondialdehyde (MDA) levels significantly increased after DEHP exposure. Western blotting revealed that DEHP exposure reduced glutathione peroxidase 4 (GPX4) expression, and elevated acyl coenzyme A synthetase long-chain member 4 (ACSL4) and lysophosphatidylcholine acyltransferase 3 (LPCAT3) expression. The in vitro results were consistent with the in vivo results. When Leydig cells and Sertoli cells were treated with ferrostatin-1 and monoethylhexyl phthalate (MEHP), MEHP-induced increases in Fe 2+ and MDA levels, accumulation of lipid reactive oxygen species, downregulation of GPX4, and upregulation of ACSL4 and LPCAT3 were reversed. Collectively, our findings suggested that aberrant lipid metabolism and ferroptosis may be involved in prepubertal DEHP exposure-induced testicular damage.
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JOURNAL OF NANOBIOTECHNOLOGY
·
2023
·Vol. 21
·期 1
·1-21
·
IF 10.2
Wang Shengmei,Guo Qiuyan,Xu Rubing,Lin Peng,Deng Guoyan,Xia Xinhua
Immunotherapy has good potential to eradicate tumors in the long term. However, due to the low immunogenicity of tumor cells, current cancer immunotherapies are not effective. To address this limitation, we constructed a BSA-FA functionalized iron-containing metal-organic framework (TPL@TFBF) that triggers a potent systemic anti-tumor immune response by inducing ferroptosis and pyroptosis in tumor cells and releasing large quantities of damage-associated molecular patterns (DAMPs) to induce immunogenicity, and showing excellent efficacy against melanoma lung metastases in vivo. This nanoplatform forms a metal-organic framework through the coordination between tannic acid (TA) and Fe 3+ and is then loaded with triptolide (TPL), which is coated with FA-modified BSA. The nanoparticles target melanoma cells by FA modification, releasing TPL, Fe 3+ and TA. Fe 3+ is reduced to Fe 2+ by TA, triggering the Fenton reaction and resulting in ROS production. Moreover, TPL increases the production of intracellular ROS by inhibiting the expression of nuclear factor erythroid-2 related factor (Nrf2). Such simultaneous amplification of intracellular ROS induces the cells to undergo ferroptosis and pyroptosis, releasing large amounts of DAMPs, which stimulate antigen presentation of dendritic cells (DCs) and the proliferation of cytotoxic T lymphocytes (CD4+/CD8 + T cells) to inhibit tumor and lung metastasis. In addition, combining nanoparticle treatment with immune checkpoint blockade (ICB) further inhibits melanoma growth. This work provides a new strategy for tumor immunotherapy based on various combinations of cell death mechanisms.
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BIOMATERIALS
·
2023
·
IF 14
Jingyuan Wang,Zekun Wang,Yuqing Li,Yajun Hou,Chenyang Yin,Endong Yang,Ziyu Liao,Cundong Fan,Lisandra L. Martin,Dongdong Sun
Alzheimer's disease (AD) as a common neurodegenerative disease showed progressive cognitive dysfunction and behavioral impairment. Currently, the deposition of amyloid β-protein (Aβ) remains the main pathomechanism. However, preventing neuronal death induced by Aβ remains elusive, and no effective strategy in clinic was found to combat AD. Herein, a multifunctional double selenium nanosphere (CLNDSe) was designed and prepared, and A 2A AR agonist (CGS) modification endowed CLNDSe NPs with A 2A AR-targeted blood brain barrier (BBB) delivery in vitro and in vivo . CLNDSe NPs after modification of LPFFD short peptide effectively inhibited Aβ 42 aggregation and attenuated Aβ 42 -induced neural toxicity by inhibiting oxidative damage and mitochondrial dysfunctions. Nerve growth factor (NGF) linked to large Se sphere significantly attenuated Tau phosphorylation and gliocytes activation in APP/PS1 mice. CLNDSe NPs administration in vivo also effectively restored GPX1/4 antioxidant ability, alleviated neural loss and neurofibrillary tangles, prevented neural ferroptosis, and eventually ameliorated cognitive deficits of APP/PS1 mice. Importantly, CLNDSe NPs showed good safety and biocompatibility. Taken together, our finding validated the rational design that BBB-targeted delivery of double selenium nanosphere may be a novel strategy to ameliorate Alzheimer's disease by inhibiting neural ferroptosis.
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FREE RADICAL BIOLOGY AND MEDICINE
·
2023
·
IF 7.4
Daohui Gong,Xueping Liu,Pengfei Wu,Yue Chen,Yuhang Xu,Zhan Gao,Hang Qian,Guansong Wang,Binfeng He
Macrophage dysfunction is a significant contributor to more than 70 % of sepsis-related deaths, specifically secondary bacterial infections, during the immunosuppression stage of sepsis. Nevertheless, the role of Rab26 in this context remains unclear. In this study, we observed a substantial decrease in Rab26 expression in macrophages during the immunosuppressive phase of sepsis, which was also found to be suppressed by high extracellular levels of HMGB1 . During the progression of sepsis, Rab26 deficiency promotes a polarization shift from the M1 to the M2-like phenotype in macrophages, rendering them susceptible to ferroptosis . Subsequent experimentation has revealed that Rab26 deficiency facilitates the degradation of GPX4, thereby aggravating macrophage ferroptosis through the upregulation of levels of lipid ROS , MDA , and ferrous iron induced by RSL3, a ferroptosis inducer. Additionally, Rab26-deficient mice in the immunosuppressed phase of sepsis exhibit heightened susceptibility to secondary infections, leading to exacerbated lung tissue damage and increased mortality rate. Overall, these findings indicate that Rab26 plays a crucial role in sepsis-induced macrophage immunosuppression by regulating macrophage ferroptosis and polarization. Hence, it represents a potential novel target for sepsis therapy.
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Applied Materials Today
·
2023
·
IF 8.3
Weimin Yin,Jiao Chang,Jiuyuan Sun,Yuge Zhao,Shiyu Chen,Hui Zhi,Jie Zang,Tingting Zhang,Yongyong Li,Haiqing Dong
Poor efficacy in solid tumor immunotherapy mainly ascribed to few CD8 + T cells infiltration with low activity in tumor immunosuppressive microenvironment (TIME). Ferroptosis can be harnessed for activating system immune response for more CD8 + T cells infiltration. However, the activity of infiltrated CD8 + T cells will be heavily weakened by the nutrient barrenness and immunosuppressive microenvironment, which formidably impaired the biologically closed-loop reciprocal process between active CD8 + T cells and cellular ferroptosis. Considering the above two key influence factors, we herein elaborately labeled l -Arginine (Arg) with 3,4-dihydroxybenzaldehyde (PA) via reversible Schiff-base bond, and then drive nanoassembly of PA-Argby iron ions mediation (Fe@PA-Arg NPs). Iron released from Fe@PA-Arg NPs in acidic tumor environment could produce reactive oxygen species (ROS) and thus successfully induce immunogenic ferroptosis of cancer cells. Subsequently, promoting the dendritic cells maturation and CD8 + T cells infiltration. Meanwhile, ROS could also induce the lipid peroxidation of tumor associated macrophages that contributed to mitochondrial dysfunction, thereby repolarized M2 to M1 phenotype to relieve the immunosuppression. Arg released from Fe@PA-Arg NPs as nutrient supply to restore infiltrated T cells’ activity by combining Arg metabolic adaption with immunosuppressive mitigation. Reciprocally, restored activated CD8 + T cells could secrete high levels of Interferon-γ, which in turn enhances ferroptosis, thereby successfully initiating and forming a closed-loop, and the tumor inhibition rate of 63.5% was achieved. This study highlights a novel and facile strategy to improve the immunotherapeutic efficiency of murine 4T1 solid tumors.
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