Journal of Pharmaceutical Analysis
·
2022
·
IF 14.026
Min Mu,Xiaoyan Liang,Na Zhao,Di Chuan,Bo Chen,Shasha Zhao,Guoqing Wang,Rangrang Fan,Bingwen Zou,Bo Han,Gang Guo
Traditional microtubule inhibitors fail to significantly enhance the effect of colorectal cancer; hence, new and efficient strategies are necessary. In this study, a supramolecular nanoreactor ( [email protected] 3+ ) based on tannic acid (TA), iron ion (Fe 3+ ), and docetaxel (DOC) with microtubule inhibition, reactive oxygen species (ROS) generation, and glutathione peroxidase 4 (GPX4) inhibition, is prepared for ferroptosis/apoptosis treatment. After internalization by CT26 cells, the [email protected] 3+ nanoreactor escapes from the lysosomes to release payloads. The subsequent Fe 3+ /Fe 2+ conversion mediated by TA reducibility can trigger the Fenton reaction to enhance the ROS concentration. Additionally, Fe 3+ can consume glutathione to repress the activity of GPX4 to induce ferroptosis. Meanwhile, the released DOC controls microtubule dynamics to activate the apoptosis pathway. The superior in vivo antitumor efficacy of [email protected] 3+ nanoreactor in terms of tumor growth inhibition and improved survival is verified in CT26 tumor-bearing mouse model. Therefore, the nanoreactor can act as an effective apoptosis and ferroptosis inducer for application in colorectal cancer therapy.
✓ 已验证
产品关联
DOI
PubMed
高影响因子
International Journal of Nanomedicine
·
2026
·
IF 8.7
Xinxin Zhang,Fengyuan Qian,Yixiang Huang,Bowen Zheng,Ziran Wang,Huanhuan Zhu,Bo Zhang
Background Colorectal cancer therapy encounters major obstacles, including insufficient tumor targeting, systemic toxicity, and the emergence of drug resistance, underscoring the need for advanced therapeutic modalities. This work aimed to engineer a multi-mechanism synergistic nanoplatform to surmount these limitations.Methods A hyaluronic acid–modified calcium phosphate nanoparticle construct (CaPHDH) was developed incorporating a dual-action mechanism via calcium ion chelation and hydrophobic entrapment. Hemin was encapsulated within the calcium phosphate lattice via a green synthesis approach, followed by electrostatic loading of doxorubicin (DOX). The nanoparticles were comprehensively characterized for physicochemical properties. Antitumor efficacy was assessed in vitro in CT26 colorectal carcinoma cells and in vivo in a CT26 tumor-bearing murine model, with or without 808 nm laser irradiation. Mechanistic investigations, including ferroptosis and immune activation, were conducted.Results The CaPHDH nanoparticles exhibited a uniform size of approximately 100 nm, excellent dispersibility, pH-triggered drug release, and high photothermal conversion efficiency. In vitro, treatment produced a markedly enhanced anti-tumor effect against CT26 cells under 808 nm laser irradiation, attributable to the synergistic actions of chemotherapy, photothermal therapy, and ferroptosis induction. In vivo, CaPHDH achieved effective tumor-specific accumulation and, upon laser irradiation, yielded superior tumor growth inhibition relative to monotherapies. In addition, CaPHDH treatment significantly promotes the polarization of tumor-associated macrophages (TAMs) toward the M1 phenotype, thereby reshaping the tumor immune microenvironment. Comprehensive biosafety assessments indicated no significant systemic toxicity, organ damage, or abnormal alterations in standard blood biochemical parameters.Conclusion This study successfully developed a biosafety-optimized nanodelivery platform, CaPHDH, which integrates chemotherapy, photothermal therapy, and ferrocide induction. This platform enables highly effective synergistic treatment in a mouse rectal cancer model, offering new insights into combination therapy strategies for tumors.
✓ 已验证
产品关联
DOI
高影响因子
PHYTOTHERAPY RESEARCH
·
2026
·
IF 8.1
Hanfei Xie,Wumin Dai,Lu Sun,Wangang Gong,Tao Zhu,Yingli Zhang
Ovarian cancer (OV) is a highly lethal gynecological tumor, often developing platinum chemotherapy resistance and treatment failure. With their diverse and complex structures, natural products offer potential solutions to drug resistance. This study systematically examines chaetocin's effects on cisplatin-resistant OV cells and its underlying molecular mechanisms. We utilized a cell counting Kit-8, transwell assays, flow cytometry, immunohistochemistry, and western blotting to evaluate chaetocin's effects on cisplatin-resistant OV cells. Proteomic analysis and bioinformatics were utilized to identify the molecular targets of chaetocin, which were validated via cell transfection and co-immunoprecipitation. Additionally, a cisplatin-resistant OV xenograft model was developed for in vivo studies. Chaetocin suppressed the malignancy of cisplatin-resistant OV cells in a dose-dependent manner to suppress cell proliferation, impede cell migration and invasion, and induce both cell apoptosis and cell cycle arrest. Furthermore, in vivo studies showed that chaetocin inhibited tumor growth in a cisplatin-resistant OV xenograft model. In terms of mechanism, chaetocin induced ferroptosis in these cells, inhibiting TFRC ubiquitination and upregulating its expression by reducing the levels of cullin1 and its neddylation binding (cullin1-NEDD8). Our study uncovers a previously unrecognized mechanism: Chaetocin induces ferroptosis by inhibiting TFRC neddylation to upregulate its expression in OV. Unlike its known role as an SUV39H1 inhibitor, chaetocin functions through the neddylation-TFRC-ferroptosis axis, a pathway not previously linked to this compound. Moreover, while neddylation has recently been reported to regulate ferroptosis via SLC7A11, our study reveals an entirely distinct mechanism involving TFRC-mediated iron transport. This epigenetic regulation stabilizes TFRC, sensitizing resistant cells to ferroptosis, providing a dual-mechanistic insight not found in existing literature. By linking chaetocin's gene regulation to iron-dependent cell death, we offer new insights and potential therapies for cisplatin-resistant OV.
✓ 已验证
产品关联
DOI
高影响因子
CYTOKINE
·
2023
·
IF 3.8
Wei Liu,Hui Zeng
Background Ulcerative colitis (UC) is a chronic and uncontrolled inflammatory bowel disease. N 6 -methyladenine (m 6 A) is a reversible mRNA modification method. IGF2BP2 is an RNA-binding protein regulated by m 6 A methylation. However, understanding of m 6 A-related proteins in UC is limited. This study was to analyze the function and related mechanism of IGF2BP2 in UC. Methods The UC models were established by dextran sulfate sodium (DSS) in NCM460 cells and mice. The expression of IGF2BP2 and GPX4 in UC were detected by qPCR and western blot. The effects of IGF2BP2 on inflammation, ferroptosis and colon injury were measured by gain- and loss-of-function experiments. This study conducted a clinical evaluation of mice using the Disease Activity Index score. The molecular mechanism of IGF2BP2 in ferroptosis were analyzed by m 6 A RNA methylation quantification kit, RNA immunoprecipitation-qPCR analysis, and RNA stability assay. Results IGF2BP2 and GPX4 were under-expressed in DSS-treated UC. IGF2BP2 enhanced the stability of GPX4 mRNA modified by m 6 A. IGF2BP2 overexpression repressed the ROS, MDA, and iron levels but enhanced the GSH and GPX4 levels in DSS-triggered NCM460 cells, which were partially reversed by GPX4 silencing. In UC mice, IGF2BP2 high-expression ameliorated symptoms, Disease Activity Index score, pathological changes, inflammatory reaction, and ferroptosis, which were also partly neutralized by GPX4 inhibition. Conclusions IGF2BP2 augmented the GPX4 expression by the m 6 A modification to weaken UC progression via suppressing ferroptosis.
✓ 已验证
产品关联
DOI
PubMed
高影响因子
PLoS Pathogens
·
2026
·Vol. 22
·期 9
·e1014644
·
IF 4.9
Yunfei Wei,Xinyu Zhao,Ziyi Yin,Yanmin Zhang,Yaxin Zhai,Baihe Zhan,Yeling Wang,Jiakang He,Jianfeng Wang,Xuming Deng,Lei Xu,Haihua Feng
Staphylococcus aureus ( S. aureus ), a major pathogen of mastitis, employs a diverse arsenal of virulence factors to invade and disrupt mammary tissues, thereby eliciting a complex and dysregulated inflammatory response. Sphingomyelin phosphodiesterase (Sph) has emerged as a key virulence determinant of S. aureus ; however, its potential role and underlying mechanisms in mastitis remain elusive. In this study, we demonstrate that Sph deficiency significantly suppresses S. aureus -induced ferroptosis. Mechanistically, Sph disrupts mitochondrial cristae through interaction with Mic60, a core component of the mitochondrial contact site and cristae-organizing system (MICOS). Sph-mediated cytosolic mitochondrial DNA (mtDNA) released is sensed by cyclic GMP-AMP synthase (cGAS), leading to activation of the STING signaling pathway, which further triggers the recruitment of GPX4 into the autophagy-lysosome pathway for degradation. Collectively, our study unveils a novel pathogenic mechanism whereby the S. aureus virulence factor Sph perturbs mitochondrial homeostasis, and engages the cGAS-STING axis to promote GPX4 degradation and ferroptosis, highlighting Sph as a potential therapeutic target for S. aureus -associated mastitis.
S. aureus is a major etiological agent of mastitis, a prevalent inflammatory disease of the mammary gland that adversely affects animal health and milk production. During infection, S. aureus deploys a diverse repertoire of virulence factors to damage host cells and promote disease progression. Among these factors, sphingomyelin phosphodiesterase (Sph) has been implicated in host cell injury; however, its contribution to mastitis pathogenesis remains poorly understood. Here, we show that Sph perturbs mitochondrial homeostasis by interacting with Mic60 and disrupting mitochondrial cristae architecture, thereby triggering activation of the cGAS-STING signaling pathway. Activated STING subsequently promotes the autophagic degradation of GPX4, a key antioxidant enzyme that protects cells against lipid peroxidation, ultimately driving ferroptotic cell death. Collectively, our findings uncover a previously unrecognized mechanism, and identify Sph as a potential therapeutic target for S. aureus -associated mastitis.
✓ 已验证
DOI
PubMed
高影响因子
Advanced Science
·
2023
·
IF 15.1
Wei Chen,Wenyu Xie,Zhimin Gao,Chen Lin,Meiling Tan,Yaru Zhang,Zhiyao Hou
A core-shell-structured Cu 2 O@Mn 3 Cu 3 O 8 (CMCO) nanozyme is constructed to serve as a tumor microenvironment (TME)-activated copper ionophore to achieve safe and efficient cuproptosis. The Mn 3 Cu 3 O 8 shell not only prevents exposure of normal tissues to the Cu 2 O core to reduce systemic toxicity but also exhibits enhanced enzyme-mimicking activity owing to the better band continuity near the Fermi surface. The glutathione oxidase (GSHOx)-like activity of CMCO depletes glutathione (GSH), which diminishes the ability to chelate Cu ions, thereby exerting Cu toxicity and inducing cuproptosis in cancer cells. The catalase (CAT)-like activity catalyzes the overexpressed H 2 O 2 in the TME, thereby generating O 2 in the tricarboxylic acid (TCA) cycle to enhance cuproptosis. More importantly, the Fenton-like reaction based on the release of Mn ions and the inactivation of glutathione peroxidase 4 induced by the elimination of GSH results in ferroptosis, accompanied by the accumulation of lipid peroxidation and reactive oxygen species that can cleave stress-induced heat shock proteins to compromise their protective capacity of cancer cells and further sensitize cuproptosis. CMCO nanozymes are partially sulfurized by hydrogen sulfide in the colorectal TME, exhibiting excellent photothermal properties and enzyme-mimicking activity. The mild photothermal effect enhances the enzyme-mimicking activity of the CMCO nanozymes, thus inducing high-efficiency ferroptosis-boosted-cuproptosis.
✓ 已验证
产品关联
DOI
PubMed
高影响因子
ACS Applied Materials & Interfaces
·
2023
·
IF 9.5
Kaixu Yu,Ying Chen,Lu Zhang,Yongqiang Zheng,Jinlin Chen,Zhenhua Wang,Xiaogang Yu,Kehan Song,Yimin Dong,Fanxiu Xiong,Zijian Dong,Hao Zhu,Gaohong Sheng,Meipeng Zhu,Xi Yuan,Hanfeng Guan,Jiaqiang Xiong,Yi Liu,Feng Li
Ferroptosis is characterized by iron accumulation and lipid peroxidation. However, a clinical dose of Fe3O4 nanoparticles could not cause effective ferroptosis in tumors, and the mechanism is yet to be completely understood. In this study, using RNA-seq data, we found that tumor cells could feedback-activate the antioxidant system by upregulating Nrf-2 expression, thus avoiding ferroptosis caused by Fe3O4 nanoparticles. We also found that DHJS (a probe for ROS generation) can antagonize Nrf-2 expression when it synergizes with Fe3O4 nanoparticles, thus inducing ferroptosis in tumor cells. Considering these findings, we created a biomimetic hybrid cell membrane camouflaged by PLGA-loaded Fe3O4 and DHJS to treat osteosarcoma. The hybrid cell membrane endowed the core nanoparticle with the extension of blood circulation life and enhanced homologous targeting ability. In addition, DHJS and Fe3O4 in nanoparticles prompted synergistically lethal ferroptosis in cancer cells and induced macrophage M1 polarization as well as the infiltration of CD8(+) T cells and dendritic cells in tumors. In summary, this study provides novel mechanistic insights and practical strategies for ferroptosis induction of Fe3O4 nanoparticles. Meanwhile, the synthesized biomimetic nanoparticles exhibited synergistic ferroptosis/immunotherapy against osteosarcoma.
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Molecular Medicine Reports
·
2023
·Vol. 28
·期 4
·1-13
·
IF 3.4
Qi Nie,Wenqing Chen,Tianmei Zhang,Shangrong Ye,Zhongyu Ren,Peng Zhang,Jian Wen
In recent years, inhibiting tumor cell activity by triggering cell ferroptosis has become a research hotspot. The development of generic targeted nanotherapeutics might bring new ideas for non‑invasive applications. Currently, the potential mechanism underlying the universal application of paclitaxel (PTX)‑loaded iron oxide nanoparticles (IONP@PTX) to different types of tumors is unclear. The present study aimed to prepare IONP@PTX for targeted cancer therapy and further explore the potential mechanisms underlying the inhibitory effects of this material on the NCI‑H446 human small cell lung cancer and brain M059K malignant glioblastoma cell lines. First, a CCK‑8 assay was performed to determine cell viability, and then the combination index for evaluating drug combination interaction effect was evaluated. Intracellular reactive oxygen species (ROS) and lipid peroxidation levels were monitored using a DCFH‑DA fluorescent probe and a C11‑BODIPY™ fluorescent probe, respectively. Furthermore, western blotting assay was performed to determine the expression of autophagy‑ and iron death‑related proteins. The experimental results showed that, compared with either IONP monotherapy, PTX monotherapy, or IONP + PTX, IONP@PTX exerted a synergistic effect on the viability of both cell types, with significantly increased total iron ion concentration, ROS levels and lipid peroxidation levels. IONP@PTX significantly increased the expression of autophagy‑related proteins Beclin 1 and histone deacetylase 6 (HDAC6) in both cell lines (P<0.05), increased the expression of light chain 3 (LC3)‑II/I in NCI‑H446 cells (P<0.05) and decreased that of sequestosome1 (p62) in M059K cells (P<0.05). Moreover, the addition of rapamycin enhanced the IONP@PTX‑induced the upregulation of Beclin 1, LC3‑II/I and HDAC6 and the downregulation of mTORC1 protein in both cell lines (P<0.05). Moreover, rapamycin enhanced the IONP@PTX‑induced downregulation of p62 protein in NCI‑H446 cells (P<0.05), suggesting that IONP@PTX induces ferroptosis, most likely through autophagy. Collectively, the present findings show that IONP works synergistically with PTX to induce ferroptosis via the autophagic pathway.
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Advanced Healthcare Materials
·
2023
·
IF 10
Yihang Ruan,Huilan Zhuang,Xuemei Zeng,Lili Lin,Xuechun Wang,Panpan Xue,Shan Xu,Qi Chen,Shuangqian Yan,Wei Huang
The colon tumor microenvironment has a high concentration of H 2 S and glutathione, which is highly immunosuppressive and adverse to multiple therapeutic methodologies such as ferroptosis. Here, an engineered microbial nanohybrid based on Escherichia coli ( E. coli ) and Cu 2 O nanoparticles to specific colon tumor therapy and immunosuppression reversion is reported. The as-prepared E. coli @Cu 2 O hybrid can accumulate in tumor sites upon intravenous injection, and Cu 2 O nanoparticles convert to Cu x S by consuming the endogenous H 2 S, which exhibits strong photothermal conversion at near-infrared II (NIR II) biological window. Furthermore, E. coli @Cu 2 O is able to induce cellular ferroptosis and cuproptosis through inactivation of glutathione peroxidase 4 and aggregation of dihydrolipoamide S-acetyltransferase, respectively. Photothermal-enhanced ferroptosis/cuproptosis achieved by E. coli @Cu 2 O reverses the immunosuppression of colon tumors by triggering dendritic cell maturation (about 30%) and T cell activation (about 50% CD8 + T cells). Concerted with immune checkpoint blockade, the engineered microbial nanohybrid can inhibit the growth of abscopal tumors upon NIR illumination. Overall, the designed microbial nanohybrid can achieve tumor-specific photothermal-enhanced ferroptosis/cuproptosis and immunosuppression reversion, showing promise in precise tumor therapy in future clinical translation.
✓ 已验证
产品关联
DOI
PubMed
高影响因子
MOLECULAR PHARMACEUTICS
·
2023
·
IF 4.9
Jingjing Chai,Jiawei Hu,Tao Wang,Xing Bao,Jiajie Luan,Yan Wang
There is an urgent need to develop efficient treatments for highly invasive triple-negative breast cancer (TNBC) with a high rate of postoperative. Baicalin (BA) has shown inhibitory effects on several tumor cells and could activate ferroptosis in some tumor cells by producing reactive oxygen species (ROS). For overcoming the shortcomings of BA in clinical applications and enhancing the effect of ferroptosis in TNBC, herein, a multifunctional liposome (BA-Fe(III) coordination-polymer-loaded liposome, BA-Fe(III) Lipo) was developed for synergistic chemotherapy of TNBC with ferroptosis activation. Fe(III) released from BA-Fe(III) Lipo could be efficiently reduced to Fe(II) in the presence of high glutathione in tumor microenvironment, which in turn catalyzed the oxidation of unsaturated fats through lipid peroxidation for more ROS production. In addition, BA-Fe(III) Lipo activated tumor cell ferroptosis by down-regulating the enzymatic activity of ferritin heavy chain 1 protein and glutathione peroxidase. This study provided a novel therapeutic strategy for the treatment of TNBC by ingeniously combining chemotherapy with the activation of ferroptosis, which presented potential clinical applications.
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Small
·
2022
·Vol. 18
·期 41
·2201704
·
IF 15.153
Yu Wang,Qinjun Chen,Haolin Song,Yiwen Zhang,Hongyi Chen,Peixin Liu,Tao Sun,Chen Jiang
Ferroptosis is a form of regulated cell death which can not only kill tumor cells but also enhance immunogenicity of tumor cells, and it is evidenced to be involved in a variety of tumor treatments, especially in cancer immunotherapy. Tumor cell-derived exosomes are reported to influence the progression and metastasis process of tumors. In the process of ferroptosis, exosomes are also demonstrated as mediators to export iron under high intracellular iron concentration and resist ferroptosis. Under this regard, the combined application of ferroptosis inducer and the inhibitor of iron-containing exosomes may enhance the ferroptosis. Herein, biocompatible hybrid nanoparticles composed of the iron oxide nanoparticles, polymers with oxaliplatin attached, and siProminin2 are constructed. The siProminin2 mediated exosomal inhibition can restore the intracellular iron concentration, which can also inhibit the secretion of tumor cell-derived exosomes. The combination of immunotherapy with oxaliplatin, ferroptosis-based cancer therapy and inhibition of tumor cell-derived exosomes can enhance the immune activation effects. The nanoparticles represent an excellent triple therapeutic strategy for enhancing ferroptosis-based cancer therapy and immunotherapy.
✓ 已验证
产品关联
DOI
PubMed
高影响因子
ADVANCED FUNCTIONAL MATERIALS
·
2023
·
IF 19
Yongjuan Li,Ningjing Lei,Xiaohan Yao,Yu Zhang,Ya Dong,Jinmeng Yi,Xinyan Li,Wenjing Deng,Guangjun Nie,Zhihai Qin
The clinical application of ferroptosis, characterized by iron-dependent lipid peroxidation, is limited because of the serious side effects of using toxic-dose iron. Herein, a polyvalent ferroptosis agonist-a hypoxia responsive polymer bearing 18-crown-6 ring (hPPAA18C6) is developed. In contrast to the natural ferroptosis agonists (erastin, RSL3, and sorafenib), hPPAA18C6 stimulates the ferroptosis by releasing endogenous iron stored in the natural “iron pools” of cellular organelles and depleting glutathione (GSH) via the benzoquinone generated from the cascade decaging reactions in hypoxia. hPPAA18C6 nanoparticle is loaded with photosensitizer-chlorine e6 (Ce6) (hPPAA18C6@Ce6) due to the inhomogeneous hypoxia microenvironment. Moreover, the exposed positively charged primary amine (NH 2 ) from hPPAA18C6 acts as an immune adjuvant, facilitating dendritic cells maturation, antigen presentation, and cytotoxic T lymphocyte activation. hPPAA18C6@Ce6 induces anti-tumor responses that are dependent on ferroptosis, photodynamics therapy (PDT), and CD8 + T-cell activity. In addition, the combination of hPPAA18C6 and Ce6 leads to combined therapeutic outcomes in primary, distant, and metastatic tumors. The activation of the ferroptosis pathway through functional polymer-hijacking endogenous iron and GSH may offer new therapeutic opportunities.
✓ 已验证
DOI
高影响因子
危险品化学品经营许可证（带存储）