Journal of Materials Chemistry B
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2025
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IF 5.7
Linye Jiang,Qingxia Wen,Yuxi Wang,Zhuoming Tan,Qiuyue Wang,Fangfang Zhang,Jingyan Ge
H2O2-activated prodrugs have been developed to alleviate the severe side effects of chemotherapy. However, achieving precise and efficient delivery, along with high activation and release efficiency at the target site, remains a significant challenge. In this study, we combined a H2O2-generating enzyme (glucose oxidase, GOx) with a H2O2-sensitive chlormethine prodrug via ‘‘reversible click’’ chemistry between amino groups on enzyme and phenyl boronic acid groups on the prodrug. The resulting enzyme-prodrug complex (G-P) was encapsulated in a glutathione (GSH)-responsive iron-based metal organic framework decorated with hyaluronic acid (HA) for tumor-targeted, synergistic ferroptosis-chemotherapy. With the assistance of HA, the resulting nanoparticles (G-P@MOF@HA) demonstrated selective intracellular delivery to CD44-overexpressed tumor cells. Once internalized, the nanoparticles disassembled in the presence of GSH, releasing the G-P complex. GOx catalyzed the conversion of glucose into sufficient H2O2, enabling in situ activation of prodrugs to elicit chemotherapy. Simultaneously, the Fenton reaction between H2O2 and Fe2+ produced cytotoxic hydroxyl radicals, amplifying ferroptosis. As a consequence, the synergistic therapy group showed superiority over monotherapy in both in vitro and in vivo anticancer studies. This work provides a more efficient and precise strategy for future cancer therapies.
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TISSUE & CELL
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2025
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IF 2.5
Houru Liu,Caiyun Zhang,Lei Zhang,Jie Shen,Kan He,Bei Huang
The high global mortality rate of lung cancer underscores the urgent need for novel therapeutic strategies. Selenium (Se), an essential trace element, exhibits tumor-suppressive properties across malignancies. This study systematically evaluated the antitumor efficacy of selenomethionine (SeMet) compared with that of selenocysteine (SeCys) in Lewis lung carcinoma (LLC) cells in vitro and in tumor-bearing mice in vivo . Compared with SeCys (IC 50 = 45.89 μM), SeMet demonstrated superior cytotoxicity against LLC cells (IC 50 = 30.19 μM) and significantly inhibited proliferation and migration by inducing apoptosis and ferroptosis. In vivo , SeMet treatment inhibited tumour growth by 50.87% through the suppression of angiogenesis, outperforming SeCys (27.3%). Transcriptomic analysis revealed the downregulation of proangiogenic chemokines ( Cxcl1 , Cxcl2 , Cxcl3 , Cxcl5 ) and the upregulation of antitumor chemokines ( Cxcl9 , Cxcl16 ) in SeMet-treated tumors. Additionally, SeMet enhanced the activity of antioxidant enzymes (T-SOD and GSH-PX) and reduced the levels of proinflammatory cytokines (IL-6 and TNF-α) without hepatorenal toxicity. These findings establish SeMet as a multifaceted therapeutic candidate for lung cancer through dual induction of apoptosis-ferroptosis and angiogenesis inhibition.
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TOXICOLOGY AND APPLIED PHARMACOLOGY
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2025
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IF 3.4
Sangping Li,Shule Tan,Xiangsheng Tian,Yiquan Ou,Shujuan Hu,Weichao Zhao,Dingxin Long
This study investigated the protective effects of resveratrol (Res) against tri-o-cresyl phosphate (TOCP)-induced spinal cord neurotoxicity in adult hens, focusing on its modulation of ferroptosis via the p62/Keap1/Nrf2 pathway. Resveratrol is a classical neuroprotective compound with antioxidant properties and the ability to activate Nrf2. Adult hens were assigned to six groups: Control, TOCP, Ferrostatin-1 (Fer-1), Ferrostatin-1 + TOCP, Resveratrol, and Resveratrol + TOCP. Spinal cord tissues were analyzed using behavioral OPIDN scoring, histology (hematoxylin–eosin and Nissl staining), biochemical assays, and Western blotting for ferroptosis- and p62/Keap1/Nrf2-related proteins. TOCP exposure induced severe ultrastructural damage, including myelin sheath disruption and neuronal degeneration, along with increased malondialdehyde (MDA) and Fe 2+ levels and decreased glutathione (GSH) and superoxide dismutase (SOD) activity. Western blot analysis demonstrated upregulation of NCOA4, ACSL4, Nrf2, P62, and LC3 II, with downregulation of GPX4, SLC7A11, FTH1, and Keap1. Resveratrol treatment significantly attenuated these molecular, biochemical, and histopathological alterations, mitigating oxidative stress and ferroptotic changes.
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Materials Today Bio
·
2025
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IF 10.2
Peng Zhang,Cuicui Li,Huichang Gao,Kunpeng Hu
Triple-negative breast cancer (TNBC), recognized as the most aggressive subtype of breast cancer, presents significant challenges in clinical management owing to the absence of effective therapeutic targets and the limitations of single-modal treatment strategies. It has been verified that rhein possesses diverse pharmacological activities, including anti-tumor and antibacterial properties, and can exert anti-cancer effects by inducing cellular ferroptosis. Meanwhile, ferroptosis of tumor cells can enhance the anti-tumor immune effect. However, the insufficient water solubility and high cytotoxicity of rhein limit its application in clinical practice. To address this challenge, we designed a rhein-iron (RH-Fe) complex and encapsulated it in a hybrid membrane (HM) derived from platelets membrane and M2 macrophages membrane to construct Rhein-Fe@HM (RF@HM) nanoparticles. The nanoparticles have appropriate particle size and good biocompatibility, which can accurately target tumor tissues. In vivo and in vitro experimental findings demonstrated that RF@HM could induce ferroptosis by regulating TP53 in tumor cells and activate the immune response of body, thereby significantly suppressing the growth of TNBC. Therefore, RF@HM-mediated ferroptosis with immunotherapy are expected to provide great potential in the clinical treatment of TNBC.
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Small Science
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2025
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IF 8.3
Shaoyi Wang,Fujian Zhang,Xiaocong Zhou,Jie Yang,Zhe Li,Songlin Li,Qunshan Lu,Houyi Sun,Peilai Liu
Osteoarthritis (OA) is a degenerative joint disease characterized by cartilage degradation. Abnormal mechanical loading exacerbates intracellular ROS accumulation and glutathione (GSH) depletion. While N -acetylcysteine (NAC) has potent antioxidant properties, its therapeutic potential in OA is limited by rapid degradation and poor intraarticular retention. In this study, chondrocyte-targeted, chondroitin sulfate (CS)-modified PLGA nanoparticles (CS-NAC-NPs) is developed for sustained and localized delivery of NAC. These nanoparticles exhibit excellent physical and chemical properties, biocompatibility, and chondrocyte targeting capabilities. In vitro, CS-NAC-NPs attenuated mechanical stress-induced ROS accumulation, preserved mitochondrial integrity, restored GSH levels, and suppressed ferroptosis, as evidenced by increased GPX4 expression and improved chondrocyte viability. In a murine model of OA, intraarticular injection of CS-NAC-NPs significantly reduced cartilage degradation and osteophyte formation, improved histological scores, and maintained extracellular matrix homeostasis more effectively than free NAC or nontargeted NAC-NPs. Notably, the therapeutic effect is abolished in GPX4-deficient mice, confirming that CS-NAC-NPs act via GPX4-mediated ferroptosis inhibition. Furthermore, in vivo tracking demonstrated excellent joint retention and no off-target toxicity, underscoring their translational safety. This study introduces a novel nanotherapeutic platform that couples biomechanical targeting with redox-responsive delivery to modulate ferroptosis, offering a promising disease-modifying approach for OA treatment.
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Frontiers in Bioscience-Landmark
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2025
·Vol. 30
·期 6
·36615
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IF 3.1
Shanli Wu,Gun Yang,Xiaosha Wen,Yi Lin,Shenglong Wang,Jing Wang,Quan Liu,Dixian Luo
Background:Aldo-keto reductase 1B10 (AKR1B10) is expressed in various malignant tissues. Several studies have highlighted the essential function of AKR1B10 in lipid metabolism and in the detoxification of lipid peroxides. The aim of this research was to explore the role of AKR1B10 in the susceptibility of MDA-MB-231 cells to ferroptosis. These cells serve as a model for triple-negative breast cancer (TNBC).Methods:Lentiviral transfection was used to establish stable cell lines with high or low expression of AKR1B10. Our model of ferroptosis used the ferroptosis activator RSL3, and the specific ferroptosis inhibitor ferrostatin-1 (Fer-1) to rescue cell death. Stable cell lines were treated with the specific inhibitor OSU-T315 directed against phosphorylation of Ser473 in protein kinase B (AKT) and Ser9 in glycogen synthase kinase 3 beta (GSK3β), either alone or in combination with RSL3. A fatty acid stress model was established using palmitic acid (PA) or arachidonic acid (AA), either in the presence or absence of serum starvation and with or without co-treatment with RSL3. Cell viability was evaluated with the cell counting kit-8 (CCK8) assay and lipid peroxidation levels by flow cytometry after staining with C11 BODIPY 581/591. Exploration of the underlying mechanisms was conducted through RNA sequencing and bioinformatics analysis. Western blotting was performed to evaluate protein levels, and quantitative real-time polymerase chain reaction (qPCR) was used to evaluate transcript levels.Results:Western blot and qPCR analyses validated the successful establishment of stable MDA-MB-231 cell lines with and without AKR1B10 overexpression. Cell viability and lipid reactive oxygen species (ROS) assays showed that AKR1B10 suppressed ferroptosis in the RSL3-induced cell death model. Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Set Enrichment Analysis (GSEA) analyses indicated the phosphatidylinositol 3-kinase (PI3K)-AKT pathway was likely to play a role in the underlying mechanisms. AKR1B10 increased the expression of glutathione peroxidase 4 (GPX4), thus potentially implicating the AKT/GSK3β/nuclear factor erythroid 2-related factor 2 (NRF2)/GPX4 pathway in the mechanism. These changes in protein levels were also observed by Western blot analysis after 6 h of RSL3 treatment. Under the influence of RSL3, the transcript levels of NRF2-related genes including GPX4, ferritin heavy chain 1 (FTH1), heme oxygenase 1 (HO-1), and NAD(P)H quinone dehydrogenase 1 (NQO-1) were significantly elevated in the AKR1B10 overexpression cell line, whereas that of prostaglandin-endoperoxide synthase 2 (PTGS2) was significantly reduced. Similar changes were observed after treatment with OSU-T315. AKR1B10 was found to suppress the sensitivity to ferroptosis induced by treatment with OSU-T315, PA, or AA. These phenomena were rescued by the ferroptosis inhibitor Fer-1.Conclusions:AKR1B10 appears to be an important mechanism protecting MDA-MB-231 cells from ferroptosis, possibly through the AKT Ser473/GSK3β Ser9/NRF2/GPX4 pathway. AKR1B10 may be a key factor underlying the therapeutic effect of RSL3 under different exogenous fatty acid microenvironments.
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Materials Today Bio
·
2025
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IF 10.2
Mingxia Zhou,Linping Lu,Xinyu Xu,Yefan Zhou,Huan Fang,Xue Wang,Dongxu Li,Xiaoyan Li,Jiaqi Hua,Jiahe Liu,Yingxia Li,Libin Jiang,Qiuju Miao,Hongtao Wen,Jing He,Shenyu Yang
Ulcerative colitis (UC), a prevalent form of inflammatory bowel disease (IBD), manifests as chronic diarrhea, abdominal pain, and bloody mucoid stools. Current treatment approaches for UC are typically limited by inadequate targeted delivery, premature gastrointestinal degradation, and systemic off-target effects. To address these challenges, we engineered PL&GA@EUK, EUK-134 nanozymes encapsulated in polylysine (PL) and glycyrrhizic acid (GA) coacervate droplets. PL&GA@EUK exhibited potent superoxide dismutase- and catalase-mimetic activities, scavenging hydroxyl radicals and demonstrating anti-inflammatory efficacy in both in vivo and in vitro models. In mice with dextran sulfate sodium-induced colitis, oral administration of PL&GA@EUK for 14 days significantly ameliorated the disease activity index and colonic damage. By maintaining the integrity of the intestinal mucosal barrier and modulating redox homeostasis, it protects the intestinal epithelial cells against ferroptosis, ultimately attenuating colitis progression. 16S rDNA sequencing revealed that PL&GA@EUK significantly enriched beneficial commensals, while suppressing opportunistic pathogens. Metabolomic analysis further indicated that it modulates lipid peroxidation-associated metabolites by regulating the biosynthesis of polyunsaturated fatty acids. Crucially, PL&GA@EUK achieved enhanced colon-targeted delivery with minimal systemic toxicity, thereby overcoming the key limitations of conventional treatments. The multifaceted mechanism of PL&GA@EUK, involving reactive oxygen species scavenging, gut microbiome remodeling, and ferroptosis suppression, underscores its immense promise for the clinical management of IBD.
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Materials Today Bio
·
2025
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IF 10.2
Ying Xiang,Jinyu Zheng,Xinlu Zhao,Lina Zhou,Qiong Yan,Yichun Ma,Yue Zhou,Ping Jiang,Yi Fang,Wenjun Li,Yinya Pan,Hongji Tao,Wenying Li,Fan Xiang,Yang Hua,Yuyi Li,Chang Zheng,Weihong Ge,Yuhong Li,Simin Yan,Yun Zhu,Guifang Xu
While much attention has been focused on the direct cytotoxic effects of anticancer agents on tumor cells, emerging evidence suggests that the induction of immunogenic cell death (ICD) and the consequent remodeling of the tumor microenvironment may critically influence overall therapeutic efficacy. Sorafenib, a multitargeted tyrosine kinase inhibitor, can induce ferroptosis and thereby trigger ICD, offering the potential to overcome chemoresistance and coordinate systemic antitumor immunity. However, its therapeutic efficacy in colorectal cancer (CRC) remains limited, attributing to its low efficiency in inducing ICD. Herein, this study investigates combined sodium butyrate (NaB) and sorafenib in liposomal co-delivery system (LipNaB@Sor) at an optimal 1:1 molar ratio in CRC. LipNaB@Sor synergistically amplifies sorafenib-induced ferroptosis and consequent ICD, concurrently activating antitumor immunity through dendritic cell maturation and cytotoxic CD8 + T cell recruitment. Mechanistically, IRF2-mediated Oasl2 downregulation activates the cGAS-STING pathway, augmenting DNA damage signaling cascades. In vivo validation demonstrates significant tumor suppression and prolonged survival without observable toxicity, establishing LipNaB@Sor as a translatable strategy to overcome therapy resistance in immunologically unresponsive CRC.
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JOURNAL OF NANOBIOTECHNOLOGY
·
2025
·Vol. 23
·期 1
·722
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IF 12.6
Ye Leiguang,Zhu Jinying,Wang Xiaoman,Chen Nianhan,Sun Ying,Zeng Xuemei,Liu Shijian,Yan Shuangqian
Overcoming therapy resistance in triple-negative breast cancer (TNBC) requires the effective targeting of cancer stem-like cells (CSCs). TNBC is characterized by hyperactivation of the mevalonate pathway, leading to cholesterol accumulation in CSC membranes, which alters membrane properties, enhances stemness, and restricts both drug penetration and lipid peroxidation-a key driver of ferroptosis. Here, we develop Fe/CDP, a nanoparticle with a Fe 3 O 4 core coated with chondroitin sulfate and loaded with pravastatin, a mevalonate pathway inhibitor, and doxorubicin (DOX). In TNBC mouse models, Fe/CDP selectively targets tumors and CSCs via CD44-chondroitin sulfate interactions, enabling localized drug release. Pravastatin suppresses cholesterol biosynthesis, restoring membrane rigidity and fluidity, thereby reducing CSC stemness, disrupting P-glycoprotein function, and downregulating ALDH1, which enhances DOX sensitivity via the EGFR/Src/HMGCR axis. Moreover, cholesterol depletion facilitates lipid peroxidation, synergizing with Fe 3 O 4 to trigger ferroptosis through CoQ10/GPX4/FSP1 downregulation. By eliminating both bulk tumor cells and CSCs, Fe/CDP provides a cholesterol-modulating strategy to overcome TNBC drug resistance. Graphical
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ANALYTICAL CHEMISTRY
·
2024
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IF 6.7
Haoyuan Geng,Panpan Chen,Yaqi Zhang,Zihan Zhu,Yanfang Zhao,Xiao Wang,Chenglong Sun
Ferroptosis, as an iron-dependent cell death mediated by lipid peroxidation, has sparked great interest in the tumor research community. Targeting ferroptosis has been proven to be a new therapeutic opportunity for inhibiting tumor growth. However, it is challenging to precisely characterize the metabolic pattern of ferroptosis in heterogeneous tumors and further identify ferroptosis-associated metabolic vulnerabilities for tumor treatment. In this work, we developed a spatiotemporally resolved method to image ferroptosis-associated metabolic alterations in 3D tumor spheroids by combining mass spectrometry imaging and stable isotope tracing techniques. The construction of a 3D tumor spheroid model allows for a more accurate simulation of ferroptosis, and the introduction of MALDI-MSI enables in situ screening of abnormal molecules in tumor tissues. Using this method, we showed that the expression proportion of nC═C = 4 polyunsaturated fatty acids, including arachidonic acid (FA-20:4) and adrenic acid (FA-22:4), were upregulated in RSL3-induced 3D tumor ferroptosis models. And the isotope tracing experiment revealed that the absorption of fatty acids and the biosynthesis of polyunsaturated fatty acids were significantly increased during ferroptosis. In addition, we discovered that arachidonic acid and adrenic acid supplementation render tumor cell sensitive to ferroptosis, thereby limiting the growth of tumor cells and the formation of 3D tumor spheroids. Such findings provide significant clues for understanding the metabolic signatures of tumor ferroptosis and raise the possibility to screen potential metabolic vulnerabilities for better tumor treatment in combination with ferroptosis.
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MOLECULAR NEUROBIOLOGY
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2024
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IF 4.6
Hou Yali,Qian Heng,Yao Ranqi,Yu Ziran,Wang Jing,Dai Jiaohua,Cui Wenqi,Li Jian,Zhao Xiujuan
Perimenopausal depression is often accompanied by metabolic disorders, which have long-term harmful effects on women’s physical and mental health. Quercetin, a kind of phytoestrogen, has anti-inflammatory, antioxidant, and nerve-protective effects, and can regulate various metabolic disorders. This study aims to investigate the effect of quercetin on hippocampal metabolic disorder in perimenopausal depression rat models based on untargeted metabolomics technology. The rat model of perimenopausal depression was established by ovariectomy combined with chronic unpredictable mild stress (OVX-CUMS). Rats with no difference in sucrose preference were randomly divided into four groups ( n = 12): sham group, OVX-CUMS group (model group), model plus quercetin group, and model plus 17β-estradiol group. At the end of the experiment, hippocampal tissues were collected for untargeted metabolomics analysis, morphological analysis, and detection of related indicators. Metabolomics identified 23 differential metabolites in the model group, and the pathway analysis discovered hippocampus metabolic abnormalities including the metabolism of arachidonic acid metabolism, glycerophospholipid metabolism, and ubiquinone biosynthesis, accompanied by an increase in oxidative stress, inflammation, and lipid peroxidation indicators. At the same time, the morphological characteristics of ferroptosis occurred in the hippocampus in the model group. These abnormal changes were reversed by treatment with quercetin or 17β-estradiol. Quercetin can improve perimenopausal depression by regulating hippocampal metabolic disorders and reducing hippocampal ferroptosis in rats. These findings provide a new strategy for the use of quercetin in the prevention and treatment of perimenopausal depression.
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International Journal of Biological Sciences
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2025
·Vol. 21
·期 11
·4872-4894
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IF 10
Chen Yuxing,Tao Yong,Huang Qiu,Xu Jingtao,Wang Zhenxin,Zhang Ye,Fu Guangxu,Tan Fuqiang,Feng Keyi,Ou Yunsheng
Osteosarcoma remains a challenging malignancy with poor prognosis, particularly in metastatic cases. This study investigates the therapeutic potential and molecular mechanisms of the Hinokitiol-iron complex (Fe(hino)3) against osteosarcoma. Fe(hino)3 induced dose-dependent cell death in osteosarcoma cell lines (HOS, 143b, and K7M2) through multiple pathways. At moderate doses, Fe(hino)3 triggered ferroptosis by disrupting mitochondrial function, enhancing ROS generation and lipid peroxidation, downregulating GSS and GPX4, and upregulating HO1 and Ferritin expression. At higher doses, Fe(hino)3 activated the NLRC4/Caspase-1/GSDMD pathway, leading to pyroptosis and the release of inflammatory factors. Mechanistically, Fe(hino)3 acted as a dual-mode cell death inducer through iron overload-mediated ferroptosis and NLRC4-dependent pyroptosis while modifying the immunosuppressive tumor microenvironment. In actual clinical application, Fe(hino)3 might be used as an alternative to chemotherapy or other targeted therapies for advanced osteosarcoma at a relatively low dose to improve biosafety and reduce side effects. However, when considering it in combination with immunotherapy for advanced osteosarcoma, a relatively safe high dose is more appropriate due to the pyroptosis-mediated inflammatory response but it still needs to consider the biosafety of combination therapy. These findings provide new insights into the development of Fe(hino)3 dose-dependent therapeutic strategies for advanced osteosarcoma treatment.
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