Brain Hemorrhages
·
2025
·
IF 1.4
Wenying Zhang,Wanyu Ma,Siying Ren,Likun Wang,Guofeng Wu
Intracerebral hemorrhage (ICH) is a severe stroke subtype with high mortality and disability. Cuproptosis is a regulatory cell death modality dependent on intracellular copper ion concentration, the role of which in ICH is unclear. Upon activation by ligand agonists, peroxisome proliferator-activated receptor-γ (PPARγ), can alleviate brain injury after ICH. To investigate the inhibitory effect of activating PPARγ on cuproptosis following ICH, we established the ICH model in vivo and in vitro and they were treated with the PPARγ agonist or antagonist after models being established successfully. Then, the copper ion concentration was measured by copper colorimetric assay and the expression of cuproptosis-related regulatory factors and copper transporter 1 was detected by western blotting and immunofluorescence staining (except in the cell level). We found that the increase in copper ion concentration following ICH leads to the disruption of copper homeostasis, inducing cuproptosis via copper toxicity. Activating PPARγ regulates the expression of cuproptosis-associated positive or negative regulatory factors and mitigates copper toxicity by inhibiting the influx of copper ions into the cell, thereby inhibiting cuproptosis. This study not only reveals the relationship between ICH and cuproptosis but also may provide new therapeutic strategies for improving the prognosis of patients with ICH.
研究领域:
神经科学
·
分子生物学
✓ 已验证
产品关联
DOI
高影响因子
BRAIN RESEARCH BULLETIN
·
2025
·
IF 3.7
Qiyu Yang,Chunyan Wang,Jingwei Cao,Zhanbin Tang,Shurong Duan
Intracerebral hemorrhage (ICH) is associated with the highest rates of mortality and residual disability. To date, effective treatments to delay or prevent ICH are still lacking. Multiple forms of neuronal cell death have been discovered following ICH, including apoptosis, necrosis, autophagy, and ferroptosis. Aldo-keto reductase family 1 member C1 (AKR1C1) has been identified to act as a protective factor in ferroptosis. However, whether AKR1C1 was involved in the development of ICH was unknown. In this study, the left cerebral striatum of the Sprague-Dawley rat was injected with collagenase type IV to induce an in vivo model. Primary rat cortical neurons treated with oxygen hemoglobin (OxyHb) were applied to as an in vitro model. AKR1C1 was found to be downregulated and immunoreactivity colocalized with NeuN-positive neurons in the perihematomal region. Rats injected with lentiviral particles overexpressing AKR1C1 showed the reduction of cerebral hematoma and the remission of blood-brain barrier disruption. Moreover, AKR1C1 upregulation repressed cell apoptosis and ferroptosis induced by ICH through downregulating the expression of pro-apoptotic factors, inhibiting iron accumulation and lipid peroxidation, along with increasing the expression of solute carrier family 7 member 11 (SLC7A11) and glutathione peroxidase 4 (GPX4). The results of in vitro assays were consistent with results from the in vivo . Mechanistically, P53 overexpression augmented the cellular damage in OxyHb-stimulated neurons when AKR1C1 was overexpressed. Taken together, AKR1C1 improves ICH injury by inhibiting neuronal cell death via negatively regulating P53 expression and affecting the SLC7A11/GPX4 pathway.
研究领域:
神经科学
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Autophagy
·
2024
·
IF 14.6
Xin Chen,Andrey S. Tsvetkov,Han-Ming Shen,Ciro Isidoro,Nicholas T. Ktistakis,Andreas Linkermann,Werner J.H. Koopman,Hans-Uwe Simon,Lorenzo Galluzzi,Shouqing Luo,Daqian Xu,Wei Gu,Olivier Peulen,Qian Cai,David C. Rubinsztein,Jen-Tsan Chi,Donna D. Zhang,Changfeng Li,Shinya Toyokuni,Jinbao Liu,Jong-Lyel Roh,Enyong Dai,Gabor Juhasz,Wei Liu,Jianhua Zhang,Minghua Yang,Jiao Liu,Ling-Qiang Zhu,Weiping Zou,Mauro Piacentini,Wen-Xing Ding,Zhenyu Yue,Yangchun Xie,Morten Petersen,David A. Gewirtz,Michael A. Mandell,Charleen T. Chu,Debasish Sinha,Eftekhar Eftekharpour,Boris Zhivotovsky,Sébastien Besteiro,Dmitry I. Gabrilovich,Do-Hyung Kim,Valerian E. Kagan,Hülya Bayir,Guang-Chao Chen,Scott Ayton,Jan D. Lünemann,Masaaki Komatsu,Stefan Krautwald,Ben Loos,Eric H. Baehrecke,Jiayi Wang,Jon D. Lane,Junichi Sadoshima,Wan Seok Yang,Minghui Gao,Christian Münz,Michael Thumm,Martin Kampmann,Di Yu,Marta M. Lipinski,Jace W. Jones,Xuejun Jiang,Herbert J. Zeh,Rui Kang,Daniel J. Klionsky,Guido Kroemer,Daolin Tang
Macroautophagy/autophagy is a complex degradation process with a dual role in cell death that is influenced by the cell types that are involved and the stressors they are exposed to. Ferroptosis is an iron-dependent oxidative form of cell death characterized by unrestricted lipid peroxidation in the context of heterogeneous and plastic mechanisms. Recent studies have shed light on the involvement of specific types of autophagy (e.g. ferritinophagy, lipophagy, and clockophagy) in initiating or executing ferroptotic cell death through the selective degradation of anti-injury proteins or organelles. Conversely, other forms of selective autophagy (e.g. reticulophagy and lysophagy) enhance the cellular defense against ferroptotic damage. Dysregulated autophagy-dependent ferroptosis has implications for a diverse range of pathological conditions. This review aims to present an updated definition of autophagy-dependent ferroptosis, discuss influential substrates and receptors, outline experimental methods, and propose guidelines for interpreting the results.Abbreviation: 3-MA:3-methyladenine; 4HNE: 4-hydroxynonenal; ACD: accidentalcell death; ADF: autophagy-dependentferroptosis; ARE: antioxidant response element; BH2:dihydrobiopterin; BH4: tetrahydrobiopterin; BMDMs: bonemarrow-derived macrophages; CMA: chaperone-mediated autophagy; CQ:chloroquine; DAMPs: danger/damage-associated molecular patterns; EMT,epithelial-mesenchymal transition; EPR: electronparamagnetic resonance; ER, endoplasmic reticulum; FRET: Försterresonance energy transfer; GFP: green fluorescent protein;GSH: glutathione;IF: immunofluorescence; IHC: immunohistochemistry; IOP, intraocularpressure; IRI: ischemia-reperfusion injury; LAA: linoleamide alkyne;MDA: malondialdehyde; PGSK: Phen Green™ SK;RCD: regulatedcell death; PUFAs: polyunsaturated fatty acids; RFP: red fluorescentprotein;ROS: reactive oxygen species; TBA: thiobarbituricacid; TBARS: thiobarbituric acid reactive substances; TEM:transmission electron microscopy.
研究领域:
细胞生物学
·
病理学
✓ 已验证
DOI
高影响因子
JOURNAL OF COLLOID AND INTERFACE SCIENCE
·
2025
·
IF 9.7
Qiao-Mei Zhou,Yuan-Fei Lu,Xiao-Yan Yang,Jin-Guo Zhang,Yi-Ning Wang,Wang-Ping Luo,Jin Mao,Jue Hou,Fan Wu,Wei-Lin Wang,Gu-Ping Tang,Hong-Zhen Bai,Ri-Sheng Yu
Hepatocellular carcinoma (HCC) presents formidable therapeutic challenges due to its pronounced metabolic heterogeneity, particularly arising from spatially uneven glucose availability within the tumor microenvironment (TME). To address this, we developed a glutathione (GSH)-responsive, biomimetic hybrid nanoenzyme system (M@GOx/Fe-HMON) composed of hollow mesoporous organosilica nanoparticles co-loaded with glucose oxidase (GOx) and Fe 2+ /Fe 3+ redox pairs, and cloaked in homologous tumor cell membranes for enhanced targeting. In glucose-rich regions, the nanoenzyme orchestrates a GOx-peroxidase (POD) cascade that produces reactive oxygen species (ROS) via the Fenton reaction, leading to ferroptosis through intensified oxidative stress and GSH depletion. Conversely, under glucose-deficient conditions, the nanoenzyme promotes disulfidptosis by aggravating glucose deprivation, depleting nicotinamide adenine dinucleotide phosphate (NADPH), and impairing cystine metabolism, ultimately resulting in actin cytoskeletal collapse. This dual-action platform dynamically adapts to the tumor’s metabolic landscape, selectively inducing ferroptosis or disulfidptosis according to glucose levels, disrupting redox homeostasis and amplifying antitumor efficacy. Notably, this study is the first to integrate ferroptosis and disulfidptosis activation into a single, metabolism-sensitive nanoenzyme system, providing a novel paradigm for exploiting tumor metabolic heterogeneity. Furthermore, the combination of endogenous metabolic regulation with magnetic resonance imaging (MRI)-guided diagnosis introduces an innovative and noninvasive strategy for precision cancer theranostics.
研究领域:
肿瘤学
·
生物化学
·
纳米医学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
BIOMATERIALS
·
2025
·
IF 12.9
Hui Zhi,Weimin Yin,Shiyu Chen,Xiaoyou Zhang,Zichen Yang,Fulong Man,Rongjie Li,Yanni Cai,Yang Li,Caoyi You,Yan Li,Yongyong Li,Haiqing Dong
Cuproptosis and ferroptosis exhibit superior synergistic advantages in antitumor therapy. While glutathione (GSH) has been identified as a key molecule in enhancing the synergistic effects of these two processes, inherent cellular redox homeostasis mechanisms limit its therapeutic efficacy. This inspired us to explore other new regulators to potentiate the synergistic effect. Through bioinformatics analysis and preliminary experimental validation, we discovered that lactate metabolism is closely associated with both ferroptosis and cuproptosis. Therefore, this work strategically targets lactate metabolism to synergistically activate cuproptosis and ferroptosis, and elucidate its immunotherapeutic mechanisms. For this purpose, we constructed a Syr-loaded nanodelivery system (Syr@mPDA@CP) using biocompatible mesoporous polydopamine (mPDA) as the carrier. Upon targeted to tumor tissues, the released Syr significantly inhibits lactate efflux, leading to intracellular lactate accumulation. This lactate buildup further induces intracellular acidification, exerting dual effects: (1) promoting ferritin (FTH1) dissociation to release endogenous iron stores, thereby elevating intracellular iron levels; and (2) suppressing glycolysis and reducing ATP levels, which inactivates the copper export protein ATP7B. Combined with copper peroxide (CP)-derived Cu 2+ , these effects synergistically amplify intracellular copper accumulation. The elevated intracellular Cu and Fe concentrations subsequently induce dual cell death pathways of cuproptosis and ferroptosis, effectively enhancing cancer immunotherapy. This study pioneers a lactate metabolism-regulating strategy to synergistically amplify both ferroptosis and cuproptosis, offering novel perspectives for antitumor therapy.
研究领域:
生物医学工程
·
肿瘤学
·
免疫学
·
生物化学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
·
2024
·
IF 6
Huiyan Hu,Fan Zhang,Zhujun Sheng,Shuang Tian,Gechang Li,Shuanghui Tang,Yajie Niu,Jiawan Yang,Yunjun Liu
This paper introduces a new ligand, 4,6-dichloro-5-(1 H -imidazo [4,5-f]phenanthroline-2-yl)pyrimidin-2-amine (DPPA), and its corresponding new iridium(III) complexes: [Ir(ppy) 2 (DPPA)](PF 6 ) (2a) (where ppy represents deprotonated 2-phenylpyridine), [Ir(bzq) 2 (DPPA)](PF 6 ) (2b) (with bzq indicating deprotonated benzo[h]quinoline), and [Ir(piq) 2 (DPPA)](PF 6 ) (2c) (piq denoting deprotonated 1-phenylisoquinoline). The cytotoxic effects of both DPPA and 2a, 2b, and 2c were evaluated against human lung carcinoma A549, melanoma B16 , colorectal cancer HCT116, human hepatocellular carcinoma HepG2 cancer cell lines, as well as the non-cancerous LO2 cell line using the 3-(4,5-dimethylthiazole-2-yl)-2,5-diphenyltetrazolium bromide (MTT) method. While DPPA exhibited moderate anticancer activity toward A549, B16, HCT116 and HepG2 cells, complexes 2a, 2b, and 2c displayed remarkable efficacy against A549, B16, and HCT116 cells. The cell colonies and wound healing were investigated. Moreover, various aspects of the anticancer mechanisms were explored. The cell cycle analyses revealed that the complexes block cell proliferation of A549 cells during the S phase. Complex 2c induce an early apoptosis, while 2a and 2b cause a late apoptosis. The interaction of 2a, 2b and 2c with endoplasmic reticulum and mitochondria was identified, leading to elevated ROS and Ca 2+ amounts. This resulted in a reduced mitochondrial membrane potential , mitochondrial permeability transition pore opening, and an increase of cytochrome c . Also, ferroptosis was investigated through measurements of intracellular glutathione (GSH), malondialdehyde (MDA), and recombinant glutathione peroxidase (GPX4) protein expression . The pyroptosis was explored via cell morphology, release of lactate dehydrogenase (LDH) and expression of pyroptosis-related proteins. RNA sequencing was applied to examine the signaling pathways . Western blot analyses illuminated that the complexes regulate the expression of Bcl-2 family proteins. Additionally, an in vivo antitumor study demonstrated that complex 2c exhibited a remarkable inhibitory rate of 58.58% in restraining tumor growth. In summary, the findings collectively suggest that the iridium(III) complexes induce cell death via ferroptosis , apoptosis by a ROS-mediated mitochondrial dysfunction pathway and GSDMD-mediated pyroptosis .
研究领域:
肿瘤学
·
药理学
·
细胞生物学
✓ 已验证
DOI
高影响因子
Nanoscale
·
2024
·
IF 5.8
Jingjing Jiang,Qiong Zhang,Yue Zhang,Lintong Gao,Yan Feng,Xianshun Sun,Junjun Wang,Xiao-Jiao Zhu,Xingxing Chen,Hong-Ping Zhou
Currently, cuproptosis mainly focuses on the Cu2+ induced morphology of mitochondria (Mito), the observation of endoplasmic reticulum (ER)-related Cu2+ content in cuproptosis is relatively lacking. Herein, we develop a hydroxyflavone (HF) based NIR excited fluorescent probe, BHCO, for exhibiting specific recognition of Cu2+. BHCO can accurately locate in ER and detect Cu2+ content in cuproptosis process. The two-photon fluorescence nature of BHCO enables to track both ferroptosis and cuproptosis processes with high resolution. Furthermore, BHCO can upgrade reactive oxygen species (ROS) under 720 nm excitation, which facilitates ferroptosis occurrence. We firmly convince the nonlinear optical (NLO) small molecules could provide a valid tool for rapid tumors elimination through synergistic ferroptosis and cuproptosis.
研究领域:
生物化学
·
肿瘤学
·
光学成像
✓ 已验证
DOI
PubMed
高影响因子
TRANSPLANTATION
·
2024
·
IF 5.3
Jia Degong,Wu Kun,Luo Jiefu,Xu Xuesong,Pan Wei,Zhao Minjie,Li Shengwei,Gong Jianping,Gong Junhua
Background. Donation after circulatory death livers are more susceptible to ischemia/reperfusion injury (IRI) because of a longer period of warm ischemia. Growing evidence now suggests that ferroptosis plays a key regulatory role in the development of IRI, so targeting ferroptosis may be an effective strategy to alleviate IRI in liver transplantation (LT). Methods. Using donation after circulatory death LT models in rats and oxygen-glucose deprivation/reoxygenation (OGD/R) models in BRL-3A cells, we tested the effect of the Chinese medicine monomer wogonin on liver IRI and explored the specific mechanism. Results. Wogonin attenuated liver IRI and increased the survival rate of rats by inhibiting lipid peroxidation and ferroptosis. Mechanistically, arachidonic acid 15-lipoxygenase-1 (ALOX15) and inducible nitric oxide synthase (iNOS) were identified as potential targets of baicalein through bioinformatics analysis combined with in vivo and in vitro experiments. This result was further confirmed by molecular docking and cellular thermal shift assays. Finally, we silenced ALOX15 and iNOS in the OGD/R cell model and found that silencing ALOX15 and iNOS could reproduce the regulatory effect of wogonin and abrogate the regulatory effect of wogonin. Conclusions. In brief, this study emphasizes that wogonin exerts a protective effect in liver IRI through the regulation of ALOX15- and iNOS-mediated ferroptosis. ALOX15 and iNOS are potential targets for intervention in IRI induced by LT, and wogonin is a drug candidate for LT patients. Export
研究领域:
移植医学
·
药理学
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Autophagy
·
2025
·
IF 14.3
Chenyu Luo,Haisheng Liang,Mintao Ji,Caiyong Ye,Yiping Lin,Yuhan Guo,Zhisen Zhang,Yinyin Shu,Xiaoni Jin,Shuangshuang Lu,Wanling Lu,Yazheng Dang,Hong Zhang,Bingyan Li,Guangming Zhou,Zengli Zhang,Lei Chang
Ferroptosis is an iron-dependent regulated form of cell death implicated in various diseases, including cancers, with its progression influenced by iron-dependent peroxidation of phospholipids and dysregulation of the redox system. Whereas the extracellular matrix of tumors provides mechanical cues influencing tumor initiation and progression, its impact on ferroptosis and its mechanisms remains largely unexplored. In this study, we reveal that heightened mechanical tension sensitizes cells to ferroptosis, whereas decreased mechanics confers resistance. Mechanistically, reduced mechanical tension reduces intracellular free iron levels by enhancing FTH1 protein expression. Additionally, low mechanics significantly diminishes NCOA4, pivotal in mediating FTH1 phase separation-induced ferritinophagy. Targeting NCOA4 effectively rescues ferroptosis susceptibility under low mechanical tension through modulation of FTH1 phase separation-driven autophagy. In conclusion, our findings demonstrate that mechanics regulates iron metabolism via NCOA4-FTH1 phase separation-mediated autophagy, thereby influencing ferroptosis sensitivity and offering promising therapeutic avenues for future exploration.
研究领域:
癌症生物学
·
细胞代谢
·
力学生物学
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Advanced Composites and Hybrid Materials
·
2024
·Vol. 8
·期 1
·1-15
·
IF 23.2
Zhang Hanyu,Xia Jing,Xie Lingling,Hao Meng,Liang Wenlong,Wang Sizhang,Dong Xiao,Li Yongxin,Mu Qiang
Cuproptosis is an emerging regulated cell death that depends on the intracellular copper ion and mitochondrial respiration, showing great potential in cancer treatment. However, increasing the specific accumulation of copper ions in mitochondria while simultaneously enhancing mitochondrial respiration is highly needed and still a major challenge to promote cuproptosis. Herein, the lactate dehydrogenase (LDH) inhibitor galloflavin (GF) self-assembles with the copper ionophore elesclomol (ES) through copper ion-driven cooperative coordination to form GF/CuES hybrid nanoparticles, synergistically targeting mitochondria and anaerobic glycolysis to boost cuproptosis-immunotherapy. After cellular internalization, the GF/CuES hybrid nanoparticles responsively dissociate to release Cu 2+ and ES, co-transporting into mitochondria to collaboratively trigger cuproptosis, which subsequently evokes immunogenic cell death (ICD). Notably, the liberated GF leads to effective LDH suppression, which not only further amplifies cuproptosis via disrupting anaerobic glycolysis and enhancing mitochondrial respiration but also reduces lactate production, thus alleviating the immunosuppressive tumor microenvironment and augmenting anti-tumor immunity driven by ICD. Thus, the GF/CuES hybrid nanoparticles exhibit strong antitumor effects through cooperatively targeting glycolysis, cuproptosis, and immunotherapy, offering a unique opportunity to enhance cancer treatment strategies.
研究领域:
肿瘤学
·
分子生物学
·
免疫学
✓ 已验证
DOI
高影响因子
CHEMICAL ENGINEERING JOURNAL
·
2024
·
IF 13.3
Xue Zhai,Tianyu Zhou,Jia Chen,Peng Su,Xinke Li,Hao Su,Biqing Bao,Lixing Weng,Lianhui Wang
Conventional immunotherapies for metastatic cancers remain highly challenging due to insufficient immunity response. Herein, we show that Pd-FePorP significantly triggers ferroptosis mediated-ICD and cooperatively reverses EMT, leading to efficient abrogation of tumor spreading, metastatic invasion and improved immunotherapy outcomes. The maximum catalytic velocity ( V max ) of Pd-FePorP was improved to ∼9.8-fold through in-situ ligand exchange strategy, which eventually induces specific ferroptosis-mediated ICD. Excitingly, Pd-FePorP reverses epithelial-mesenchymal transition (EMT) by upregulating cytokeratin and E-cadherin through inhibition of PI3K/AKT signaling pathway, which could thus interrupt the metastasis cascade to significantly inhibit primary tumor cells migration and invasion. In mouse model, the pretreatment with Pd-FePorP induces EMT reversal in tumor cells, thereby impeding their recolonization in lung tissues and leading to 99 % reduction in lung metastasis nodules. Additionally, when combined with ICD effect induced by ferroptosis, Pd-FePorP synergistically improves the immunosuppressive microenvironment in primary tumor, resulting in effective inhibition of lung metastasis. Our approach may open a new avenue to explore nanozyme as synergistic therapeutic strategy through cooperation between catalysis of smart nanozyme system and EMT reversal for combating cancer metastasis.
研究领域:
肿瘤学
·
免疫学
·
纳米医学
✓ 已验证
产品关联
DOI
高影响因子
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.
研究领域:
肿瘤学
·
生物化学
·
纳米医学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）