Science Advances
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2025
·Vol. 11
·期 20
·
IF 12.5
Hanxi Zhang,Jiazhen Lv,Hao Wu,Yuhan He,Mengyue Li,Chunhui Wu,Dong Lv,Yiyao Liu,Hong Yang
Apoptosis resistance and immune evasion of tumor cells substantially increase the risk of cancer treatment failure. Here, a multifunctional nanozyme MET-CMS@FeTA (MCMSFT) formulated to induce nonapoptotic ferroptosis and boost immune recognition/attack, where compensatory mechanisms collectively overcome intrinsic tumor therapeutic limitations and improve medical intervention outcomes. Leveraging the multienzyme-like activity of MCMSFT to achieve oxygen generation, hydroxyl radical production, and glutathione depletion promotes hypoxia relief and triggers apoptosis/ferroptosis. Notably, MCMSFT-mediated photothermal therapy (PTT) facilitates direct tumor thermal ablation and offers exogenous heat to accelerate nanocatalytic reactions. Furthermore, PTT/ferroptosis-caused immunogenic cell death favors antitumor immunity initiation. Simultaneously, metformin administration and hypoxia amelioration down-regulate programmed death ligand 1 alleviating immune evasion. Interferon-γ secretion poses positive feedback to ferroptosis, thereby establishing a ferroptosis-immune mutual amplification loop. Antitumor performances illustrate that MCMSFT eliminates primary tumors and suppresses metastasis/rechallenge tumors. Collectively, MCMSFT surmounts the predicament of apoptosis resistance and immune evasion in cancer treatment to acquire more effective and comprehensive therapy efficacy.
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Environmental Chemistry and Ecotoxicology
·
2025
·
IF 8.2
Bin Liu,Cun-Long Wang,Teng-Zhou Li,Jian-Xue Feng,Yu-Qing Ma,Ling Liu,Ping Li,Zhi-Hua Li
Tralopyril has emerged as a promising alternative to the banned tributyltin in marine antifouling applications. However, its ecological risks remain underestimated. Through an integrated approach combining behavioral phenotyping, transcriptomics, and whole-genome bisulfite sequencing (WGBS), we demonstrate that tralopyril (0, 1, 10 μg/L) disrupts marine medaka ( Oryzias melastigma) development via two interrelated mechanisms: (1) Epigenetic dysregulation: Aberrant CG methylation in key regulatory genes ( casr , cacna2d2 , dnai1 , alox15b , etc.) was associated with developmental toxicity, altering gene expression profiles critical for normal growth. (2) Ferroptosis activation: Tralopyril exposure triggered iron overload and fth1 dysregulation, while mitochondrial uncoupling ( ucp2 ) exacerbated oxidative stress, contributing to cellular damage. Notably, epigenetic alterations, such as methylation changes in alox15b , can influence the ferroptosis pathway by regulating genes involved in iron metabolism and oxidative stress. This, in turn, amplified toxic effects and contributed to multiorgan damage. These alterations led to defects such as cardiac remodeling, skeletal malformations, and neuromuscular dysfunction, ultimately resulting in locomotor decline. Inhibitor rescue experiments identified critical molecular targets of tralopyril's toxic effects and demonstrated cross-regulation between ucp2 expression and the ferroptosis pathway. These findings elucidate the key molecular mechanisms underlying tralopyril-induced developmental abnormalities and behavioral impairments, emphasizing the synergistic effects of mitochondrial dysfunction and ferroptosis. Overall, this study expands the understanding of mitochondrial function and ferroptosis in environmental toxicology and provides a scientific basis for ecological risk assessment and mitigation strategies for environmental pollutants.
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Antioxidants
·
2025
·Vol. 14
·期 5
·576
·
IF 6.6
Jiaming Chen,Yuting Fu,Shaoping Weng,Jianguo He,Chuanfu Dong
Scale drop disease virus (SDDV) poses an escalating threat to global aquaculture, prompting an urgent need for research. Our study found that SDDV infection upregulates genes related to iron, oxidative stress, and lipid metabolism, causing iron overload, reactive oxygen species (ROS) accumulation, and ultimately ferroptosis. Among the tested antioxidants, vitamin C (VC) demonstrated the most potent inhibitory effect in mandarin fish, reducing SDDV-induced mortality by 37.5%. qPCR and IFA results showed that VC effectively suppressed SDDV infection; decreased ROS, lipid peroxidation (LPO), and iron levels; and enhanced glutathione peroxidase 4 (GPX4) expression in infected cells. Mechanistically, VC’s inhibitory effect was reversed by the nuclear factor erythroid 2-related factor 2 (Nrf2) inhibitor ML-385, indicating an Nrf2-dependent pathway. VC promoted Nrf2 nuclear translocation and activated downstream antioxidant genes. Moreover, VC modulated inflammation by regulating pro- and anti-inflammatory factors. These findings suggest VC as a promising therapeutic for SDDV infection.
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CHEMICAL ENGINEERING JOURNAL
·
2025
·
IF 13.2
Bowen Jia,Yuchen Yao,Yejia Xu,Yang Zhao,Jing Li,Yumeng Wu,Xiaofeng Zeng,Shijun Hong,Qianqian Li,Xuexia Liu,Chengliang Luo
Traumatic brain injury (TBI) is a major global health issue, causing blood–brain barrier disruption, neuroinflammation, and neuronal damage. Current therapies are limited and failed to address key pathological mechanisms like ferroptosis, oxidative stress, and inflammation, highlighting the need for novel treatments. Recent advances in nanomedicine, particularly nanozymes, offer promising solutions. Copper-based ultrasmall nanozymes, with excellent catalytic activity and biocompatibility, have shown potential in mitigating ferroptosis and oxidative stress. In this study, we developed polyethylene glycol-modified Cu 5.4 O (Cu 5.4 O-PEG), a nanomaterial with superior blood–brain barrier penetration and biocompatibility. Cu 5.4 O-PEG demonstrated no cytotoxicity and significantly reduced oxidative stress and ferroptosis in both in vitro and in vivo models, improving motor and cognitive functions in murine TBI models. The therapeutic effects were mediated through multiple mechanisms, including inhibition of the Fenton reaction, scavenging of reactive oxygen species (ROS), and reducing iron deposition, effectively limiting tissue damage. Proteomic analysis revealed modulation of ferroptosis-related proteins and activation of protective pathways related to transferrin receptor 1 (TfR1). Furthermore, using AAV-mediated knockdown of TfR1 in mice, we observed significant reductions in lipid peroxidation markers such as ACSL4, COX2, and 4HNE, indicating a decrease in iron-induced damage. Histological analysis showed reduced iron deposition, and improved neuronal morphology in TfR1 knockdown mice underwent TBI, indicating knockdown of TfR1 could alleviate TBI-indued ferroptosis and iron-dependent neurodegeneration. Taken together, these data imply that Cu 5.4 O-PEG presents a neuroprotective strategy for improving cerebral recovery after TBI, at least partly by inhibiting TfR1-mediated ferroptosis.
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JOURNAL OF CONTROLLED RELEASE
·
2025
·
IF 11.5
Fei Wu,Chunxue Song,Hanxiao Yin,Ronglong Chen,Guanyu Huang,Jiajun Zhang,Haimin Chen,Li Lin,Junqiang Yin,Lisi Xie,Weihai Liu
Poor bioavailability and dose-limiting cardiotoxicity persistently hinder the clinical application of bufalin (BF). Conventional BF-based nanoagents have shown promise in tackling these challenges, yet advanced nanostrategies with further improved performance and clinical accessibility still await development. Herein, we introduce a novel cooperative nanoparadigm based on disulfide-linked bufalin homodimeric prodrugs (SBF) and metal phenolic networks (MPNs). This strategy achieves high drug-loading capacity and structural stability. Stability perturbation experiments reveal that hydrophobic interactions, electrostatic adsorption, and coordination bonds synergistically drive co-assembly of SBF and MPNs. The resultant nanopartieles (MSBNAs) exhibit prolonged circulation kinetics, tumor-selective accumulation, and pH/GSH dual-responsive properties, effectively mitigating BF-induced cardiotoxicity. Further antitumor mechanistic investigations unveil that MSBNAs amplify BF-induced ferroptosis through a dual assault of oxidative stress and iron overload induced jointly by MPNs-delivered exogenous iron and BF-triggered endogenous iron. This increased ferroptosis endows MSBNAs with superior suppression of tumor growth and lung metastasis, maintaining excellent biocompatibility without cardiotoxicity. Our work not only establishes a promising candidate platform to surmount the therapeutic hurdles of BF but also enriches the design landscapes of co-assembled nanomedicines, thereby laying a foundation for the clinical translation of BF and other antitumor drugs.
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INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
·
2022
·Vol. 24
·期 1
·229
·
IF 6.208
Mao Huang,Xinru Cao,Yucong Jiang,Yuehong Shi,Yazhen Ma,Dandan Hu,Xingju Song
Toxoplasma gondiiis a widespread intracellular pathogen that infects humans and a variety of animals. Dihydroartemisinin (DHA), an effective anti-malarial drug, has potential anti-T. gondiiactivity that induces ferroptosis in tumor cells, but the mechanism by which it killsT. gondiiis not fully understood. In this study, the mechanism of DHA inhibitingT. gondiigrowth and its possible drug combinations are described. DHA potently inhibitedT. gondiiwith a half-maximal effective concentration (EC50) of 0.22 μM. DHA significantly increased the ROS level of parasites and decreased the mitochondrial membrane potential, which could be reversed by ferroptosis inhibitors (DFO). Moreover, the ferroptosis inducer RSL3 inhibitedT. gondiiwith an EC50of 0.75 μM. In addition, RSL3 enhanced the DHA-induced ROS level, and the combination of DHA and RSL3 significantly increased the anti-Toxoplasmaeffect as compared to DHA alone. In summary, we found that DHA-induced ROS accumulation in tachyzoites may be an important cause ofT. gondiigrowth inhibition. Furthermore, we found that the combination of DHA and RSL3 may be an alternative to toxoplasmosis. These results will provide a new strategy for anti-Toxoplasmadrug screening and clinical medication guidance.Keywords:Toxoplasma gondii;dihydroartemisinin;ferroptosis inducer RSL3;mitochondrial membrane potential;ROS
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ACS Applied Bio Materials
·
2020
·
IF 0
Min Mu,Yuelong Wang,Shasha Zhao,Xiaoling Li,Rangrang Fan,Lan Mei,Min Wu,Bingwen Zou,Na Zhao,Bo Han,Gang Guo
Chemotherapy works against tumors by inducing cell apoptosis; however, evasion of apoptosis is recognized to result in resistance to anticancer therapy. Ferroptosis is an iron-dependent cell death pathway that differs from apoptosis in morphological, biochemical, and genetic levels. Combined ferroptosis and apoptosis may shed light on strategies for cancer treatment. Therefore, we have designed a nanoparticle (NP) that can simultaneously cause tumor cell apoptosis and ferroptosis. This NP is composed of epigallocatechin gallate (EGCG) and Fe3+ through a simple and green process and can be used to deliver doxorubicin hydrochloride (DOX) and iron ions to the tumor site at the same time. DOX/Fe3+/EGCG (DF) NPs display a great resolubility and long-term storage stability, and efficient DOX and Fe3+ release is realized after cellular internalization under the high level of glutathione and acidic nature in tumor. EGCG is likely to chemically reduce the released Fe3+ to Fe2+. The generated Fe3+/Fe2+ converts intracellular H2O2 to hydroxyl radicals (•OH) via the Fenton reaction. In addition, the generated •OH subsequently induces lethal ferroptosis to improve DOX-induced apoptosis. In vitro and in vivo investigations indicate that a great therapeutic effect was achieved, suggesting that the formation of the DF NP delivery system is a promising strategy to fight against tumors by an apoptosis and ferroptosis combination modality.
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Translational Cancer Research
·
2025
·Vol. 14
·期 11
·7641
·
IF 1.7
Yuan Cheng,Liu Ruiwen,Xu Xinming,Sun Jun,Zhu Yi,Lu Rongzhu,Liu Yueyu,Chen Jian
Background Because of the high malignancy and subtle early symptoms of hepatocellular carcinoma (HCC), most patients lose the opportunity for surgery and opt for drug therapy. However, the current drugs for HCC treatment remain suboptimal, underscoring the urgent need to develop a novel anti-HCC agent. Curcumin is a natural chemical compound that has anti-cancer effects on various tumor cells, attracting sustained attention from researchers and clinicians. The present study aims to further elucidate curcumin’s anti-HCC mechanisms, thereby offering a promising therapeutic candidate for HCC patients. Methods The viability of HCC cells was evaluated by Cell Counting Kit-8 (CCK-8) assay. The levels of glutathione (GSH), malondialdehyde (MDA), and total iron in the cells were detected by biochemical kits. The levels of reactive oxygen species (ROS) and Fe 2+ in the cells were detected by fluorescent probes. The protein expressions of protein kinase RNA-like endoplasmic reticulum kinase (PERK), nuclear factor erythroid 2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1), and glutathione peroxidase 4 (GPX4) in the cells were detected by western blotting. Results Curcumin exerted a notably suppressive impact on HCC cells, which could be reversed by ferrostatin-1 (Fer-1) and desferrioxamine (DFO). By detecting cellular metabolic products, we observed an increase in total iron, Fe 2+ , MDA, ROS, and a reduction in GSH levels in HCC cells after treatment with curcumin, and these effects could be attenuated by Fer-1. Western blot analysis showed that curcumin significantly downregulated GPX4 levels in HCC cells while upregulating PERK, Nrf2 and HO-1 expression. Additionally, using PERK inhibitor, HO-1 inhibitor, and endoplasmic reticulum (ER) stress inhibitor could partially reverse the inhibition of HCC cells viability by curcumin and alleviate the reduction of GPX4 expression caused by curcumin. Conclusions Curcumin may induce ferroptosis in HCC cells through the PERK/Nrf2/HO-1 signaling pathway, thereby exerting its anti-cancer effects, suggesting that curcumin could potentially be used as a drug for treating HCC.
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Small
·
2025
·
IF 12.1
Jinglang Gong,Hongxiang Huang,Maoyu Gao,Yiling Ruan,Ruifang Chen,Yaoting Li,Shouju Wang,Xiaolian Sun
Nanometal-based therapies face challenges arising from the overexpression of proton efflux transporters in cancer cells, which acidifies the extracellular tumor microenvironment (TME) while preserving a relatively neutral intracellular pH, thereby compromising therapeutic efficacy and fostering an immunosuppressive TME. Here, we integrate the proton pump inhibitor pantoprazole (PTZ) with manganese ferrite nanoparticles (MFNs) within an acidity-responsive polymer for enhanced ferroptosis and cGAS-STING activation mediated immunotherapy. This assembly (PTZ/MFNAs) facilitates tumor accumulation through the enhanced permeability and retention effect while initially restricting the release of metal ions. Upon reaching the tumor site, PTZ release increases intracellular acidity, which further triggers assembly disintegration, accelerates the release of iron and manganese ions, and neutralizes the extracellular microenvironment to alleviate immunosuppression. The released manganese ions synergistically collaborate with iron ions to amplify reactive oxygen species (ROS) generation for ferroptosis while activating the cyclic guanosine monophosphate-adenosine monophosphate synthase-stimulator of interferon genes (cGAS-STING) pathway, stimulating innate immunity. This potentiation of innate immunity, coupled with the reversal of TME immunosuppression, collectively and effectively inhibits tumor growth and metastasis. Therefore, the PTZ/MFNAs co-delivery system represents a promising pH-modulation strategy to enhance iron/manganese ions-mediated ferroptosis and cGAS-STING activation-induced immunotherapy.
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CURRENT MEDICINAL CHEMISTRY
·
2024
·
IF 3.5
Shang JingJing,Xiong Chenwei,Jiang Wei,Yu Zhentang,Zhang Junjie,Zhang Yi,Han Long,Miao Kaisong,Yu Changlin,Huang Yong,Zhou Xindie
Background: Osteoarthritis (OA) is a chronic joint disease, usually accompanied by degeneration
of the articular cartilage, fibrosis, bone hyperplasia around the joint, and damage to the
entire articular surface. Gossypol is a natural phenolic compound isolated from the seed of cotton
plants, and gossypol acetic acid (GAA) is a medicinal form of Gossypol. Recently, various biological
activities of GAA, including anti-inflammatory and anti-tumor effects, have been widely reported.
However, its effect on chondrocytes in OA has yet to be determined.
Methods: In this study, we investigated the effect of GAA on ferroptosis in OA chondrocytes. The
effect of GAA on the cell viability and cytotoxicity of chondrocytes in rat cells was investigated
using CCK8. Western blotting, Reverse-transcription PCR (RT-PCR), and immunofluorescence
staining were used to elucidate the molecular mechanisms and signaling pathways of GAA inhibition
of ferroptosis in OA chondrocytes. The effect of GAA on reactive oxygen species (ROS) production
and lipid peroxidation levels in chondrocytes was examined using dihydroethidium (DHE)
staining and fluorescent dye BODIPY581/591 C11. in vivo, micro-CT imaging, hematoxylin
and eosin staining, Safranin O-Fast staining, and immunohistochemistry were performed to evaluate
the effects of GAA on OA cartilage.
Results: The results showed that GAA treatment regulated the expression of chondrocyte extracellular
matrix (ECM) related factors, including ADAMTS5, MMP13, SOX9, Aggrecan, and
COL1A2 and reduced the ROS and lipid peroxidation levels. Besides, Erastin could reverse the effects
of GAA on chondrocytes. Similar to GAA, 5-AZA caused the reduction of ROS and lipid
peroxidation levels and reversed the effect of IL-1β on the expression of ECM-related factors in
OA chondrocytes. The above results clarified that GAA alleviated the ferroptosis of chondrocytes
in OA by inhibiting GPX4 methylation.
Conclusion: Our findings revealed that GAA might be developed as a drug for treating OA clinically.
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JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY
·
2025
·
IF 6.2
Jie Zhou,Yurou Li,Chen Xi,Wupei Pan,Qin Yu,Zhengping Wu
Fumonisin B1 (FB1) is a common mycotoxin known to cause hepatotoxicity in various species. However, whether ferroptosis is involved in its toxicity remains unclear, and effective interventions are lacking. Apigenin (AG) is a natural antioxidant with recognized cytoprotective properties. In this study, we investigated ferroptosis in FB1-induced liver injury and explored AG’s protective effects via the Nrf2/FSP1 pathway. FB1 triggered ferroptosis in hepatocytes, evidenced by decreased ubiquinol (CoQ10H2), Nrf2, and ferroptosis suppressor protein 1 (FSP1) levels, and increased Fe2+ levels, NAD+/NADH ratio, and lipid peroxidation (LPO). Both ferrostatin-1 and AG attenuated FB1-induced ferroptosis by upregulating CoQ10H2 and suppressing LPO, with effects similar to those of Nrf2 or FSP1 overexpression. However, knockdown of either Nrf2 or FSP1 abolished AG’s protective effects against FB1-induced ferroptosis. Collectively, this study reveals a novel mechanism by which AG activates the Nrf2/FSP1 pathway to counteract FB1-induced hepatotoxicity, suggesting its potential as a hepatoprotective agent against environmental toxins.
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Theranostics
·
2026
·Vol. 16
·期 16
·9185
·
IF 14.9
Shulin Du,Moyi Zhang,Hao Zheng,Ran Gao,Jinrong Chen,Rouyu Lin,Jing Li,Mengsi Zhang,Hao Zhang
The adaptive regulation of abnormal redox homeostasis endows tumor cells with robust survival capabilities, with glutathione (GSH) serving as one of the antioxidant cornerstones, which significantly impairs the efficacy of many regulated cell death-related therapies, including disulfidptosis and ferroptosis.
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