FREE RADICAL RESEARCH
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2025
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IF 2.9
Lihong Zhou,Xiaodan Zhang,Yulong Peng,Shiyu He,Zhen Mao,Jin Cai,Hong Yang,Peili Huang
Wilson’s disease (WD) is an autosomal recessive disorder associated with impaired copper metabolism that results in hepatic manifestations. However, as a rare disease, the underlying pathogenic mechanism and drug development have lagged behind. Studies have reported that copper accumulation is associated with potential increases in iron levels, which can lead to further exacerbation of oxidative damage and has been observed in WD patients. Therefore, removing excess copper from the body and enhancing antioxidant capacity are crucial in treatment. Melatonin (MLT) is an endogenous hormone with anti-oxidative stress, anti-inflammatory, and anti-ferroptosis properties, and can chelate transition metals. Thus, the study aimed to investigated the relationship between WD and ferroptosis, and the therapeutic efficacy and mechanism of MLT using copper-laden rats and HepG2 cell models. Our results suggested that copper overload significantly increased oxidative stress and altering ferroptosis-related metabolites of the liver in copper-laden rats. In vivo and in vitro experiments showed that copper overload disrupts the ceruloplasmin-ferroportin (Cp-Fpn) iron transport system, leading to increased iron levels and promoting ferroptosis, as indicated by the decreased levels of ferroptosis-related proteins GPX4, with these findings further supported by RSL3 and Ferrostatin-1. Further, we found that MLT could improve liver function, iron levels and enhance its antioxidant capacity. In addition, MLT was also able to inhibit ferroptosis by activating the Nrf2/SLC7A11/GPX4 pathway. The effect is more effective than penicillamine, the current therapeutic drugs.Key Policy HighlightsCopper overload induces hepatic ferroptosis in Wilson’s disease via iron accumulation, glutathione depletion, and lipid peroxidation.Reduced ceruloplasmin disrupts the ferroportin-mediated iron efflux system, aggravating ferroptosis.Melatonin alleviates liver injury and copper accumulation by inhibiting ferroptosis via activation of the Nrf2/SCL7A11/Gpx4 pathway.
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Science Advances
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2024
·Vol. 10
·期 15
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IF 11.7
Kerong Chen,Anwei Zhou,Xinyuan Zhou,Jielei He,Yurui Xu,Xinghai Ning
Disruptions in metal balance can trigger a synergistic interplay of cuproptosis and ferroptosis, offering promising solutions to enduring challenges in oncology. Here, we have engineered a Cellular Trojan Horse, named MetaCell, which uses live neutrophils to stably internalize thermosensitive liposomal bimetallic Fe-Cu MOFs (Lip@Fe-Cu-MOFs). MetaCell can instigate cuproptosis and ferroptosis, thereby enhancing treatment efficacy. Mirroring the characteristics of neutrophils, MetaCell can evade the immune system and not only infiltrate tumors but also respond to inflammation by releasing therapeutic components, thereby surmounting traditional treatment barriers. Notably, Lip@Fe-Cu-MOFs demonstrate notable photothermal effects, inciting a targeted release of Fe-Cu-MOFs within cancer cells and amplifying the synergistic action of cuproptosis and ferroptosis. MetaCell has demonstrated promising treatment outcomes in tumor-bearing mice, effectively eliminating solid tumors and forestalling recurrence, leading to extended survival. This research provides great insights into the complex interplay between copper and iron homeostasis in malignancies, potentially paving the way for innovative approaches in cancer treatment.
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MOLECULAR NEUROBIOLOGY
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2025
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IF 4.3
Li Xinying,Li Weiran,Xie Xinying,Fang Ting,Yang Jingwen,Shen Yue,Wang Yicheng,Wang Hongyan,Tao Liqing,Zhang Heng
Rotenone, a plant-derived natural insecticide, is widely used to induce Parkinson’s disease (PD) models. However, the mechanisms of rotenone-induced cell death remain unclear. Here, we found that rotenone (0.01, 0.1, or 1 μmol/L) suppressed SH-SY5Y dopamine neuron viability and led to PD-like pathological changes, such as reduced tyrosine hydroxylase (TH) but increased α-synuclein. Rotenone increased the levels of intracellular reactive oxygen species (ROS) and mitochondrial ROS, as well as the levels of the antioxidants nuclear factor E2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1), ultimately resulting in oxidative stress. Moreover, rotenone significantly downregulated the expression of GPX4 and xCT but upregulated the expression of COX2 and NCOA4, which are markers of ferroptosis. Furthermore, rotenone decreased phosphorylated mTOR level but increased Beclin-1, ATG5, LC3 and p62 expression, suggesting that rotenone enhances autophagy and reduces autophagy flux. Additionally, rotenone reduced Bcl-2 levels and the mitochondrial membrane potential (MMP) while promoting BAX and Caspase-3 expression, thus initiating cell apoptosis. N-acetylcysteine (NAC), a ROS scavenger, and ferrostatin-1 (Fer-1) and deferoxamine (DFO), two ferroptosis inhibitors, significantly eliminated rotenone-induced autophagy and apoptosis. Moreover, ML385, a specific inhibitor of Nrf2, suppressed rotenone-induced ferroptosis. Our results demonstrated that ROS might mediate rotenone-induced PD-like pathological changes by regulating iron death, autophagy, and apoptosis. Inhibiting ferroptosis blocked the rotenone-induced increase in autophagy and apoptosis. Thus, the ability of ROS to regulate rotenone-induced death through autophagy and apoptosis is dependent on ferroptosis. The findings require validation in multiple neuronal cell lines and in vivo.
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JOURNAL OF MEDICINAL CHEMISTRY
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2025
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IF 6.8
Qing-Hua Shen,Long-Bo Yu,Shan-Ming Yao,Zhi-Yuan Li,Qi-Qi Zhang,Peng Wang,Cai-Ping Tan
Metalloenzyme mimics based on small molecules are valuable therapeutic candidates, but there are few reports on their mechanism of action. Inspired by natural enzymes, we designed two Cu–Fe bimetallic multienzyme mimetics (CuFc1 and CuFc2). Due to the coordination of the bimetallic centers, CuFc1 exhibits mimetic activities for multiple enzymes, including peroxidase (POD), catalase (CAT), superoxide dismutase (SOD), and glutathione oxidase (GSHOx). CuFc1 can catalyze cascade reactions from •O2– and H2O2 to O2 and •OH, which leads to a storm of reactive oxygen species and causes cuproptosis and ferroptosis in cancer cells simultaneously. As CuFc1 treatment upregulates the expression of PD-L1, it acts synergistically with the PD-L1 inhibitor (BMS-1) to remodel the tumor immune microenvironments and stimulates intense anticancer immune responses in vivo. In summary, through reasonable molecular design, we first demonstrate the enormous potential of metallo small molecule-based multienzyme mimics in cancer immunotherapy.
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Journal of Materials Chemistry B
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2025
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IF 5.7
Wei Zheng,Yan Zhu,Qian Chen,Shuhan Shi,Qi Huang,Xinhua Chen,Xiawei Li,Pu Cheng,Haibin Wu,Shen Hu
Bis-allylic hydrogen atoms from polyunsaturated fatty acids (PUFAs) in biological membranes are major initiation sites of ferroptosis. However, the location of PUFAs in the hydrophobic interior of the lipid bilayer makes it challenging for most ferroptosis-inducing drugs interact with PUFAs to promote lipid peroxidation (LPO), potentially limiting the occurrence of ferroptosis. Here, we propose a new generalized method named physical-chemical cascade ferroptosis (PCCF) strategy for triggering ferroptosis by disrupting the integrity of the cell membrane to expose bis-allylic hydrogen atoms that react with nanozyme MnFI under nanosecond pulses electric field (nsPEF) assistance. In vitro, PCCF continuously depletes GSH and produces LPO, inducing catalytic efficiency improvement, and collaboratively ferroptosis occurs through the GSH-mediated GPX4 pathway in triple-negative breast cancer (TNBC). In vivo, PCCF possesses a significant tumor growth inhibitory potential through ferroptosis and increases CD8+ T cells and CD4+ T cells infiltration and DC cell maturation in tumor tissues. At the same time, the PCCF platform inhibits TNBC lung metastasis in mice. This work raises a novel TNBC therapeutic strategy that exposes PUFAs to react with nanozyme to directly trigger LPO production with nsPEF assistance and stimulate ferroptosis-mediated tumour immune efficacy.
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CHEMICO-BIOLOGICAL INTERACTIONS
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2024
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IF 4.7
Jiaqi Li,Dezhi Chen,Jialiang Suo,Jiaqi Li,Yimu Zhang,Yu Wang,Zhewen Deng,Qi Zhang,Bo Ma
Triptolide (TP) is a major bioactive compound derived from Tripterygium wilfordii Hook . F . (TwHF) known for its medicinal properties, but it also exhibits potential toxic effects. It has been demonstrated to induce severe male reproductive toxicity, yet the precise mechanism behind this remains unclear, which limits its broad clinical application. This study aimed to investigate the mechanisms underlying testicular damage and spermatogenesis dysfunction induced by TP in mice, using both mouse models and the spermatocyte-derived cell line GC-2spd. In the present study, it was found that TP displayed significant testicular microstructure damaged and spermatogenesis defects including lower concentration and abnormal morphology by promoting ROS formation, MDA production and restraining GSH level, glutathione peroxidase 4 (GPX4) expression in vivo . Furthermore, Ferrostatin-1 (FER-1), a ferroptosis inhibitor, was found to significantly reduce the accumulation of lipid peroxidation, alleviate testicular microstructural damage, and enhance spermatogenic function in mice. Besides, notably decreased cell viability, collapsed mitochondrial membrane potential, and elevated DNA damage were observed in vitro . The above-mentioned phenomenon could be reversed by pre-treatment of FER-1, indicating that ferroptosis participated in the TP-mediated spermatogenesis dysfunction. Mechanistically, TP could enhance GPX4 ubiquitin degradation via triggering K63-linked polyubiquitination of GPX4, thereby stimulating ferroptosis in spermatocytes. Functionally, GPX4 deletion intensified ferroptosis and exacerbated DNA damage in GC-2 cells, while GPX4 overexpression mitigated ferroptosis induced by TP. Overall, these findings for the first time indicated a vital role of ferroptosis in TP induced-testicular injury and spermatogenic dysfunction through promoting GPX4 K63-linked polyubiquitination, which hopefully offers a potential therapeutic avenue for TP-related male reproductive damage. In addition, this study also provides a theoretical foundation for the improved clinical application of TP or TwHF in the future.
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JOURNAL OF NANOBIOTECHNOLOGY
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2025
·Vol. 23
·期 1
·1-17
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IF 12.6
Liu Suyi,Sun Kunhui,Li Mengnan,Liu Xinyue,Wang Ping,Li Meifang,Peng Bo,Wang Bing,Chang Yan-xu,Yu Xie-an
Ferroptosis is emerging as a promising therapeutic strategy for glioblastoma (GBM). However, insufficient lipid peroxidation levels and blood-brain barrier (BBB) pose a significant challenge for GBM treatment. Here, we present natural product luteolin (Lut)-coordinated Fe3+ nanoparticles loaded with dihydroartemisinin (DHA), designated as FLD NPs, which can cross the BBB and induce quadruple amplified ferroptosis. Specifically, FLD NPs leverage four mechanisms to enhance ferroptosis: (1) Lut upregulates heme oxygenase 1 (HO-1), promoting heme degradation and recruiting endogenous Fe2+. (2) exogenous Fe3+ depletes glutathione (GSH), increasing Fe2+ levels and catalyzing H2O2 to generate ·OH via the Fenton reaction; (3) Fe2+ facilitates the cleavage of DHA’s peroxide bridge, further elevating ·OH production; and (4) Lut-coordinated Fe3+ acts as a photothermal agent, accelerating the Fenton reaction under light irradiation. Furthermore, FLD NPs enable multimodal imaging capabilities, including photoacoustic and photothermal imaging, for precise tumor targeting. It demonstrates satisfactory antitumor efficacy in GBM models, highlighting its potential as a novel ferroptosis-amplifying nanotherapeutic. Importantly, this study reveals that Lut modulates tight junction protein expression in vascular endothelial cells, facilitating BBB penetration. This work highlights a novel strategy for GBM therapy, leveraging natural product-mediated nanoparticles to amplify ferroptosis.
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Bioactive Materials
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2025
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IF 20.3
Xin Pang,Chang Zhang,Qicai Xiao,Yi Cheng,Qixuan Dai,Hu Chen,Sijia Tan,Gang Liu,Yun Zeng
Biofilm formation poses a severe challenge to antibacterial stewardship. While siderophore-antibiotic conjugates (termed as sideromycins) offer a promising solution, their efficacy is inherently limited by antibiotic resistance. To transcend this barrier, we pioneer a transformative siderophore-sonosensitizer conjugate through covalent linkage of a catechol siderophore to purpurin 18 (a sonosensitizer). This novel conjugate further self-assembles with iron(III) ions, forming the first-reported carrier-free nanosideromycin—an all-in-on iron-siderophore-sonosensitizer nanoplatform. This design enables ultrasound-denotated reactive oxygen species (ROS) generation and ferroptosis-like amplication. Capitalizing on bacteria-specific siderophore uptake and pH-responsive assembly/disassembly, the nanosideromycin enables precision delivery and active internalization of sonosensitizers into bacteria. This strategy permits real-time localization of infections via concurrent fluorescence/photoacoustic and magnetic resonance imaging. Upon ultrasound irradiation, dual antimicrobial mechanisms of sonosensitizer-mediated sonodynamic therapy and siderophore/iron-augmented sono-Fenton catalysis are stimuonously unleashed, synergistically tirggering an explosive ROS burst and potent ferroptosis-like bacterial death. As a result, mice with multidrug-resistant biofilm-induced pyomyositis were completely cured. Collectively, this first-in-class theranostic nanosideromycin integrates highly-targeted imaging diagnostics, cost-effective yet ultra-efficient ROS generation, and ferroptosis-like bacterial killing, establishing a paradigm-shifting strategy for biofilm therapy with spatiotemporal controllability.
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CELL BIOCHEMISTRY AND BIOPHYSICS
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2025
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IF 2.5
Wang Hong,Li Feilong,Mei Yongliang,Wu Taotao,Wang Liquan,Hao Pandeng,Ci Shenjing,Liu Zongchao
Intervertebral disc degeneration (IVDD), characterized by lower back pain, is a prevalent chronic orthopedic disease imposing significant physical and economic burdens. However, the molecular mechanisms of IVDD remain insufficiently explored, hindering clinical guidance. This study aimed to identify key targets of IVDD via bioinformatics, providing new therapeutic directions. Gene expression profiles GSE34095 and GSE150408 were retrieved from public databases, and IVDD-related gene datasets were obtained from GeneCards and CTD. Protein-protein interaction (PPI) networks were constructed, followed by functional enrichment analyses using Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), Reactome Pathway Knowledgebase (Reactome), and WikiPathways. Key genes associated with the ferroptosis pathway were screened, and the effect of resveratrol on IVDD was validated via in vitro and in vivo experiments. Enrichment analyses identified ferroptosis as the major signaling pathway in IVDD. Six key genes (Glutathione Peroxidase 4 (GPX4), Transferrin receptor (TFRC/TFR1), Solute Carrier Family 7 Member 11 (SLC7A11/xCT), Hypoxia Inducible Factor 1 Subunit Alpha Gene (HIF1A), Interleukin-6 (IL6), and Interleukin-1 Beta (IL1B)) were selected. In vitro studies showed that resveratrol inhibited ferroptosis in nucleus pulposus cells (NPCs), while in vivo experiments in rats confirmed that resveratrol alleviated IVDD by regulating ferroptosis-related genes. Molecular docking validated the binding of resveratrol to these key targets. This study demonstrates that resveratrol delays IVDD progression by inhibiting ferroptosis in NPCs, providing a novel therapeutic strategy for clinical IVDD prevention and treatment.
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FREE RADICAL BIOLOGY AND MEDICINE
·
2025
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IF 8.2
Wei Guangji,Peng Huixin,Hu Hongfei,Lan Hai,Feng Yang,Luo Shihua,Huang Yanxin,Yuan Huixiong,Chen Wencheng
Aluminum (Al) is a pervasive environmental contaminant with detrimental biological effects. Although Al exposure induces oxidative stress and toxicity in spermatogenic cells, leading to impaired male reproductive function, the underlying molecular mechanisms remain incompletely elucidated. In this study, we systematically evaluated the toxic effects of Al on spermatogenic cells using both in vivo and in vitro models. Transcriptomic profiling of GC-2spd cells revealed Al-induced differential gene expression related to oxidative stress response, iron homeostasis, and lipid metabolism regulation. These alterations were notably enriched in the ferroptosis and HIF-1 signaling pathways. Subsequent in vivo analyses demonstrated that Al exposure increased iron levels and oxidative stress while reducing ATP content in mouse testes, resulting in testicular damage, decreased sperm quality, and lowered serum sex hormone levels, all of which contribute to reproductive dysfunction. Further investigations confirmed that Al disrupts redox and iron homeostasis, promoting lipid peroxidation and ferroptosis in both mouse testes and GC-2spd cells. Importantly, administration of the ferroptosis inhibitor Ferrostatin-1 (Fer-1) effectively restored homeostasis, thereby alleviating Al-induced ferroptosis and spermatogenic cell toxicity. In conclusion, this study demonstrates that Al disrupts iron and redox balance, leading to iron accumulation and lipid peroxidation in spermatogenic cells, which triggers ferroptosis and ultimately causes male reproductive impairment. These findings identify ferroptosis as a novel therapeutic target for mitigating aluminum-related reproductive risks and provide a scientific basis for public health interventions in occupational and environmental settings grounded in this newly characterized cell death mechanism.
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Materials Today Bio
·
2025
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IF 10.2
Hui Liu,Xiaochuan Yang,Xianwen Liang,Ying Xia
The hindrance posed by the blood-brain barrier (BBB) and the unique characteristics of the tumor microenvironment (TME) remain major challenges in glioblastoma (GBM) therapy. Here, we developed a dual-magnetically driven ultrasmall Mo 0.2 Fe 2.8 O 4 @CeO x /FA (MFCF) nanozyme exhibiting multienzyme catalytic activities for targeted synergistic therapy of GBM. This nanozyme demonstrated dual responsiveness to alternating magnetic fields (AMF) and static magnetic fields, synergized with folic acid (FA)–mediated molecular targeting to enhance BBB penetration and achieve high-precision GBM localization. Upon simultaneous exposure to AMF and near-infrared (NIR) laser irradiation, MFCF amplified reactive oxygen species (ROS) generation, depleted glutathione, and alleviated hypoxia through synergistic magnetothermal effects, type-II photodynamic therapy, and its intrinsic multienzyme catalytic activities, ultimately inducing both ferroptosis and apoptosis. Notably, this hybrid cell-death pathway triggered immunogenic cell death, promoting the proliferation and differentiation of T cells and thereby achieving systemic immune activation. Concurrently, it reprogrammed M2-polarized macrophages into pro-inflammatory M1 phenotypes, remodeling the immunosuppressive TME and enhancing antitumor immunotherapy. Furthermore, the excellent superparamagnetism of MFCF enabled T 2 -weighted magnetic resonance imaging (MRI)-guided treatment monitoring. Overall, this work presents a multifunctional nanoplatform that overcomes BBB and TME barriers to enable precise, immunomodulatory therapy for GBM.
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JOURNAL OF TRACE ELEMENTS IN MEDICINE AND BIOLOGY
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2025
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IF 3.3
Siqi Hua,Shuangshuang Song,Chunhao Yang,Jingwen Xu,Zhonghua Li,Bo Zhu,Zichun Hua
Background Ferroptosis has emerged as a critical pathogenic mechanism in ulcerative colitis (UC). Metallothioneins (MTs), known for their redox regulatory functions, may protect against ferroptosis in UC. However, the underlying mechanisms are still unclear. Methods We conducted comprehensive investigations combining a bioinformatics analysis of a human UC dataset (GSE243625) with experimental validations using DSS-induced murine colitis models and RSL3-treated HCT116 human colon epithelial cells. Our experimental approaches included immunohistochemical analysis of MT2 expression, assessment of ferroptosis markers, evaluation of mitochondrial function, measurement of mitochondrial redox status and Fe 2+ , and profiling of protein expression. The therapeutic potential of ZnO nanoparticles was evaluated in vivo . Results Transcriptomic analysis revealed significant downregulation of all nine MT family members in UC patients, with the most pronounced suppression occurring in active disease. This finding was corroborated in murine models, which showed reduced colonic MT2 expression following DSS treatment. Cellular studies demonstrated that MT2A overexpression provides robust protection against RSL3-induced ferroptosis, evidenced by a reduction in lipid peroxidation, preservation of mitochondrial integrity, and decreased accumulation of mitochondrial reactive oxygen species. Mechanistically, MT2A modulated cellular iron homeostasis by downregulating transferrin receptor (Tfrc). Importantly, the oral administration of ZnO nanoparticles effectively restored MT2 expression, downregulated Tfrc, attenuated ferroptosis, and significantly alleviated colitis symptoms in vivo. Conclusions Our findings establish MT2A as a crucial regulator of ferroptosis in UC pathogenesis and identify ZnO nanoparticle-mediated MT2 induction and Tfrc downregulation as a promising therapeutic strategy. This study provides novel insights into the MT2A-ferroptosis axis and its potential translational applications for UC treatment.
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