ACS Applied Materials & Interfaces
·
2025
·
IF 8.2
Yulong Liu,Jun Wang,Ziqi Wang,Kang Yang,Liqin Jiao,Xiaoqian Bu,Jun Ma,Hongfang Shao,Bin Song,Ruiping Zhang
Ferroptosis therapy efficacy in cancer is seriously restricted by the overexpression of glutathione (GSH) and hypoxia. Herein, a hypoxia-activated biodegradable porphyrin-based covalent organic framework (HPCOF) loading l-buthionine sulfoximine (BSO) and Fe3+, followed by modification with hyaluronic acid (HA), is fabricated (BFCOF) for antitumor therapy through multiple regulatory pathways. BFCOF could produce singlet oxygen (1O2) and hydroxyl radicals (·OH), which not only induce apoptosis and necrosis but also promote lipid peroxidation (LPO) accumulation, resulting in ferroptosis. The loaded BSO could block the biosynthesis of GSH, combined with the self-cycling valence alternations of Fe3+/Fe2+, and the intracellular GSH is consumed and decreased, which results in the inactivation of glutathione peroxidase 4 (GPX4) and the accumulation of LPO, eventually inducing synergistically enhanced ferroptosis. The ferroptosis dominated by the above reactions synergizes with BFCOF-mediated photothermal therapy to improve the efficacy of cancer therapy. Moreover, the reaction between Fe3+ and H2O2 also produces O2, alleviating tumor hypoxia. Importantly, BFCOF has a response to the tumor microenvironment and could be degraded for clearance, exhibiting excellent biosafety. The obtained BFCOF presents a new strategy for effectively improving ferroptosis efficiency and multimodal cancer therapies.
✓ 已验证
产品关联
DOI
PubMed
高影响因子
BMC Medicine
·
2025
·Vol. 23
·期 1
·1-18
·
IF 8.3
Wang Shuang,Xu Le,Jiao Xue,Dong Xiaoyu,Zhong Zhaoyang,Ren Qianhui,Liu Xiaoxuan,Yuan Ming,Wang Guoyun
Background Endometriosis (EM) exhibits localised iron overload. However, the contribution of ferroptosis to EM pathogenesis remains unclear. We investigated how iron overload affects CD8⁺ T cell immune function and the underlying ferroptotic mechanisms. Methods We collected eutopic and ectopic endometrial tissues from 57 patients with stage III–IV EM and eutopic tissues from 31 controls. Iron deposition was assessed by Prussian blue staining; CD8⁺ T cell infiltration by immunohistochemistry; and ferroptosis in CD8⁺ T cells by immunofluorescence and flow cytometry. In vitro and in vivo assays measured CD8⁺ T cell ferroptosis and endometrial stromal cell apoptosis via flow cytometry. Transwell assays evaluated cell migration. Gene and protein expression were analysed via RT-qPCR and Western Blot. We verified the effect of iron overload on the growth of lesions in vivo by constructing a mouse EM model. The role of CD8⁺ T cells in EM progression was tested using a reinfusion model. Results In ectopic EM lesions, CD8⁺ T cells were enriched yet functionally impaired, showing increased ferrous iron accumulation and lipid peroxidation alongside decreased GPX4 expression. In vitro, iron overload reduced CD8⁺ T cell viability, elevated lipid peroxidation, and induced mitochondrial damage—effects reversed by ferroptosis inhibitors. Iron overload upregulated p53 and downregulated xCT and GPX4; p53 inhibition blocked ferroptosis, indicating a p53-dependent pathway. In vivo EM models confirmed that excess iron compromises CD8⁺ T cell function and impairs their recruitment to lesion sites. Conclusions Iron overload induces p53-mediated inhibition of xCT/GPX4, triggering ferroptosis in CD8⁺ T cells and leading to their dysfunction. These insights into ferroptosis–CD8⁺ T cell interactions in EM may guide the development of novel immunotherapeutic strategies. Graphical abstract
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Materials Today Bio
·
2026
·
IF 11
Mian Yu,Yuanqi Liu,Jiayin Yu,Shengjie Sun,Yanling Chen,Yixuan Fang,Yuk Chin Angel Chung,Xuande Zhu,Hui Cai,Meiying Wu
Copper exerts opposing effects on immunogenic ferroptosis. • Driving PUFA remodeling, siC@CuPP overcomes copper-induced metabolic ferroptosis resistance. • Copper-mediated inhibition of extracellular GPX4 release is preserved in siC@CuPP. • siC@CuPP-mediated potent antitumor immunity suppresses primary tumors and distant metastasis. Ferroptosis is an immunogenic form of regulated cell death with considerable potential for cancer immunotherapy, yet its efficacy is frequently limited by adaptive resistance mechanisms. Here, we uncover a previously unrecognized bidirectional role of copper-based ferroptosis inducers in breast cancer. On the one hand, copper suppresses the release of extracellular GPX4, an immunosuppressive damage-associated molecular pattern, preserving the immunostimulatory effects of ferroptotic cell death. On the other hand, copper-induced ferroptotic stress activates carnitine palmitoyltransferase 1A (CPT1A)-dependent fatty acid oxidation, which limits polyunsaturated fatty acid (PUFA) availability and reduces ferroptosis susceptibility. To overcome this adaptive metabolic resistance, we developed siC@CuPP, a polyethylenimine-modified copper-doped polypyrrole nanocomplex that delivers Cpt1a siRNA while retaining the intrinsic ferroptosis-inducing activity of the CuPPy core. siC@CuPP efficiently silenced Cpt1a , inhibited fatty acid oxidation-driven PUFA consumption, promoted lipid remodeling, and impaired NADPH replenishment, thereby enhancing oxidative stress and ferroptosis sensitivity. Concurrently, copper-mediated suppression of extracellular GPX4 relieved ferroptosis-associated immunosuppression and facilitated dendritic cell activation. These coordinated effects established a positive feedback loop between immunogenic ferroptosis and antitumor immunity through interferon-γ–ACSL4 signaling. In an orthotopic 4T1 triple-negative breast cancer model, systemic administration of siC@CuPP elicited robust antitumor immune responses, significantly suppressing primary tumor growth and pulmonary metastasis. Collectively, this work identifies CPT1A-dependent metabolic adaptation and extracellular GPX4-mediated immunosuppression as two notable barriers to immunogenic ferroptosis and provides a coordinated strategy for overcoming both, thereby amplifying ferroptosis-driven cancer immunotherapy. Download: Download high-res image (577KB) Download: Download full-size image
✓ 已验证
DOI
高影响因子
Journal of Advanced Research
·
2024
·
IF 11.4
Guiqin Huang,Yawen Cai,Menghui Ren,Xiaoyu Zhang,Yu Fu,Run Cheng,Yingdi Wang,Mingxing Miao,Lingpeng Zhu,Tianhua Yan
Introduction Triple-negative breast cancer (TNBC) is the primary cause of breast cancer-induced death in women. Literature has confirmed the benefits of Salidroside (Sal) in treating TNBC. However, the study about potential therapeutic targets and mechanisms of Sal-anchored TNBC remains limited. Objective This study was designed to explore the main targets and potential mechanisms of Sal against TNBC. Methods Network pharmacology, bioinformatics, and machine learning algorithm strategies were integrated to examine the role, potential targets, and mechanisms of the Sal act in TNBC. MDA-MB-231 cells and tumor-bearing nude mice were chosen for in vitro and in vivo experimentation. Cell viability and cytotoxicity were determined using CCK-8, LDH test, and Calcein-AM/PI staining. Antioxidant defense, lipid peroxidation, and iron metabolism were explored using glutathione, glutathione peroxidase, malondialdehyde (MDA), C11-BODIPY 581/591 probe, and FerroOrange dye. Glutathione peroxidase 4 (GPX4) or stearoyl-CoA desaturase 1 (SCD1) overexpression or nuclear receptor co-activator 4 (NCOA4) deficiency was performed to demonstrate the mechanism of Sal on TNBC. Results The prediction results confirmed that 22 ferroptosis-related genes were identified in Sal and TNBC, revealing that the potential mechanism of the Sal act on TNBC was linked with ferroptosis. Besides, these genes were mainly involved in the mTOR, PI3K/AKT, and autophagy signaling pathway by functional enrichment analysis. The in vitro validation results confirmed that Sal inhibited TNBC cell proliferation by modulating ferroptosis via elevation of intracellular Fe 2+ and lipid peroxidation. Mechanistically, Sal sensitized TNBC cells to ferroptosis by inhibiting the PI3K/AKT/mTOR axis, thereby suppressing SCD1-mediated lipogenesis of monounsaturated fatty acids to induce lipid peroxidation, additionally facilitating NCOA4-mediated ferritinophagy to increase intracellular Fe 2+ content. The GPX4 or SCD1 overexpression or NCOA4 deficiency results further supported our mechanistic studies. In vivo experimentation confirmed that Sal is vital for slowing down tumor growth by inducing ferroptosis. Conclusions Overall, this study elucidates TNBC pathogenesis closely linked to ferroptosis and identifies potential biomarkers in TNBC. Meanwhile, the study elucidates that Sal sensitizes TNBC to ferroptosis by SCD1-mediated lipogenesis and NCOA4-mediated ferritinophagy, regulated by PI3K/AKT/mTOR signaling pathways. Our findings provide a theoretical basis for applying Sal to treat TNBC.
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF CONTROLLED RELEASE
·
2025
·
IF 11.5
Ka Hong Wong,Yixuan Wang,Xinwei Wang,Yuying Yin,Kun Feng,Meiwan Chen
Glutathione peroxidase 4 (GPX4) and dihydroorotate dehydrogenase (DHODH) are two mitochondrial cellular defense systems that operate in parallel to protect against ferroptosis. Simultaneously deactivating both proteins can initiate lipid peroxidation, leading to ferroptosis and subsequent cell death. In this study, we developed a transferrin-modified liposomes (TDPL) doped with unsaturated fatty acid docosahexaenoic acid (DHA) as a lipid peroxidation inducer and encapsulated piperine (PIP) to realize effective anticancer therapy. Specifically, transferrin serves a dual role in this system, acting as both a ligand targeting transferrin receptors and a Fe 3+ ionophore. Triggered by the low pH in the lysosome, Fe 3+ ions bound to transferrin are released and reduce to Fe 2+ , which can subsequently catalyze the peroxidation of unsaturated fatty acid. Meanwhile, DHA incorporated into the lipid bilayer of the liposome, can fuse with the cell membrane and deactivate GPX4 and thus inducing lipid peroxidation. Furthermore, PIP functions as a potent DHODH inhibitor. Such combination prevents the detoxification of lipid hydroperoxides by GPX4 and the suppression of lipid peroxyl radical production by DHODH. Collectively, this straightforward system promotes antitumor efficacy of unsaturated fatty acid DHA and drug molecule PIP by inhibiting ferroptosis protection mechanisms to induce lipid peroxidation.
✓ 已验证
产品关联
DOI
PubMed
高影响因子
BIOCHEMICAL PHARMACOLOGY
·
2025
·
IF 5.6
Tianfeng Yang,Suyu Zhang,Kun Nie,Xiuhong Peng,Jian Huo,Xiao Fu,Yanmin Zhang
Although ferroptosis as an emerging way exhibits tremendous promising in the therapy of hepatocellular carcinoma (HCC), the novel therapeutic agents targeting ferroptosis are still scarce. In our previous study, we found that the natural products toosendanin (TSN) possessed significant anti-proliferative efficacy by regulating WW domain-containing oxidoreductase (WWOX) in HCC. However, there is very limited understanding about TSN-induced ferroptosis, and the role of WWOX in ferroptosis has not been studied. In present study, we investigated the effect and underlying molecular mechanisms of TSN in WWOX-mediated ferroptosis in HCC. We found that TSN induced ferroptosis in HCC cells and its effect was dependent on WWOX. RNA-seq and RT-qPCR assay identified that TSN significantly increased spermidine/spermine N1-acetyltransferase 1 (SAT1) expression while decreased solute carrier family 40 member 1 (SLC40A1) expression, which play vital roles in ferrous ion transport. Further dual-luciferase reporter assay and Co-IP assay revealed that TSN-induced WWOX activation controlled the transcriptional activity of p53 and NF-E2-related factor 2 (NRF2) by regulating their interaction. Meanwhile, IF assay and WB assay confirmed that TSN increased the nuclear distribution of p-WWOX and p-p53 dimers, but impeded the nuclear translocation of NRF2 by inducing its ubiquitination degradation, ultimately regulating the transcription of their downstream target genes. In addition, the results from cell viability assay and the tumor xenograft model verified that co-treatment of TSN, ML385 (NRF2 inhibitor), and MIRA-1 (p53 activator) could effectively inhibit HCC cells growth in the presence of Fer-1 (ferroptosis inhibitor) in vitro and in vivo. Overall, our study contributes to the necessary understanding of the molecular mechanisms of WWOX-mediated ferroptosis regulation, and identifies TSN as a potential therapeutic agent targeting ferroptosis for HCC.
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Cell Death & Disease
·
2025
·Vol. 16
·期 1
·1-16
·
IF 9.6
Yang Mengxue,Wang Ting,Shao Jingrong,Ran Xinna,Xiao Rui,Zhao Rui,Wu Chunyan,Ji Ming,Tian Weiping,Sun Huabing,Liu Jiao,Zuo Shengkai
Myocardial infarction (MI) remains one of the leading causes of mortality worldwide, and cardiomyocyte death plays a critical role in cardiac remodeling after MI. Ferroptosis is a recently identified form of iron-dependent programmed cell death that has been shown to be involved in the progression of various cardiovascular diseases, including MI. Bromodomain-containing protein 4 (BRD4) is an epigenetic reader and a key regulator of cell survival. In this study, we screened an epigenetic target library containing 773 small-molecule compounds and found that (+)-JQ-1(hereafter abbreviated as JQ-1), a BRD4-specific inhibitor, markedly attenuated ferroptosis induced by erastin (a ferroptosis inducer) in cardiomyocytes. Both prophylactic and therapeutic JQ-1 administration significantly improved cardiac remodeling and reduced cardiomyocyte ferroptosis in mice with MI. Mechanistically, JQ-1 protected cardiomyocytes from erastin-induced ferroptosis by downregulating the expression of nicotinate phosphoribosyltransferase (NAPRT) and upregulating the expression of nicotinamide phosphoribosyltransferase (NAMPT) and sirtuin1 (SIRT1). Inhibition of NAMPT or SIRT1 abrogated the protection conferred by JQ-1 in erastin-treated H9C2 cardiomyocytes. The combination of proteolysis-targeting chimeras (PROTACs) with JQ-1 (JQ-1-PROTAC) promoted BRD4 protein degradation and rescued erastin-induced ferroptosis in H9C2 cardiomyocytes, and prevented erastin-induced ferroptosis in human cardiomyocytes. Thus, JQ-1 can protect cardiomyocytes from ferroptosis through the NAMPT-SIRT1 pathway, and JQ-1-based therapy may serve as a novel promising strategy to improve cardiac remodeling after MI.
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF NANOBIOTECHNOLOGY
·
2025
·Vol. 23
·期 1
·1-21
·
IF 12.6
Pei Mingliang,Guan Xin,Hou Xiaodong,Niu Zhiyuan,Lyu Qi,Wang Kai,Wang Shanshan,Zhang Jingkai,Ke Yun,Zhuang Shuting,Chen Jie,Xu Huixiong,Yang Fan
Currently, given variations in the abnormal tumor microenvironment (TME), significant progress has been made in the treatment of breast cancer (BC) based on TME-responsive nanosystems-mediated ferroptosis. Due to inherent deficiencies such as the limited efficacy of Fe-induced catalysis, the lack of endogenous hydrogen peroxide (H 2 O 2 ), and the overexpression of glutathione (GSH) in tumor cells, the treatment of ferroptosis is restricted. Here, this document highlighted polymeric nanoparticles with GSH resection (ssP-tHB@Fe/DOX), demonstrating significant improvements in TME responses, biocompatibility, and anti-tumor effects. Our study offers a platform for combined BC amplification therapy involving ferroptosis and DOX-induced chemotherapy, and it highlights the use of 3,4,5-trihydroxybenzaldehyde (tHB) in a Fe(III)-Fe(II) cyclic reaction to deplete GSH and enhance ferroptosis. Notably, ssP-tHB@Fe/DOX could effectively disrupt mitochondrial structure and reduce membrane potential in tumor cells, leading to decreased ATP production, depletion of GSH via multi-channel approach, inhibition of GPX4 expression, and accumulation of lipid peroxidation, thereby inducing ferroptosis enhancement to achieve BC therapy. Meanwhile, the release of the anticancer drug DOX has dual effects: it interferes with NADPH to enhance the Fe-mediated Fenton reaction and induces apoptosis in tumor cells. Moreover, RNA sequencing (RNA-seq) analysis robustly supported the anti-tumor mechanism of ssP-tHB@Fe/DOX, confirming involvement in the amino acid metabolism ferroptosis signaling pathway and the p53 signaling pathway, etc. Therefore, in this study, we thoroughly introduced the design of intelligent nanosystems, proposed methods to enhance DOX-induced apoptosis and ferroptosis, offering a novel approach for cancer treatment.
✓ 已验证
产品关联
DOI
PubMed
高影响因子
ADVANCED FUNCTIONAL MATERIALS
·
2025
·
IF 19
Yuchen Zhang,Shuang Feng,Jie Luo,Kaige Xu,Junfeng Guo,Xingyue Zhang,Mengxue Yuan,Qiang Luo,Yu Huang,Chaoqiang Fan,Kibret Mequanint,Donghui Zhu,Malcolm Xing,Shiming Yang
The cGAS-STING signaling pathway effectively activates antitumor immune responses and holds promise for overcoming drug resistance in hepatocellular carcinoma (HCC) immunotherapy. However, achieving specific activation of this pathway in HCC remains challenging. Here, it is introduced a single-metal-doped nanoplatform, ZMRPF, which leverages ferroptosis-induced mitochondrial DNA (mtDNA) release to stimulate cGAS-STING-mediated immune activation. ZMRPF initiates HCC ferroptosis by inducing high levels of lipid reactive oxygen species, leading to mitochondrial stress and the release of endogenous mtDNA. This mtDNA synergistically activates the cGAS-STING pathway, enhanced by immunoactivating Mn 2 ⁺ ions released from ZMRPF. Concurrently, the tumor antigens released during ferroptosis amplify the activity of antigen-presenting cells, creating a cascade that links ferroptosis with innate immunity. This cascade drives a robust systemic antitumor immune response, effectively reversing the immunosuppressive microenvironment of HCC. These results demonstrate the ability of ZMRPF to reshape the immune microenvironment of HCC and offer a promising strategy for next-generation tumor immunotherapy.
✓ 已验证
产品关联
DOI
高影响因子
Materials Today Bio
·
2025
·
IF 10.2
Jing Wang,Yixian Liu,Rong Rong,Xiaobo Xia
Glaucoma, a leading cause of irreversible blindness, is characterized by progressive retinal ganglion cell (RGC) degeneration with limited treatment options. The natural flavonoid farrerol exhibits neuroprotective potential through antioxidative and anti-inflammatory effects, but its therapeutic application is limited by poor bioavailability and photodegradation. This study investigates farrerol's neuroprotective mechanisms and develops an optimized nanoformulation for enhanced efficacy. In vitro oxygen-glucose deprivation/reperfusion (OGD/R) and in vivo ischemia-reperfusion (IR) models demonstrate that farrerol significantly improves RGC survival and visual function. Mechanistic studies reveal that farrerol activates the nuclear factor erythroid 2-related factor 2 (Nrf2) antioxidant pathway, reduces reactive oxygen species (ROS) accumulation, and modulates key ferroptosis markers (glutathione peroxidase 4 (GPX4) and acyl-CoA synthetase long-chain family member 4 (ACSL4)), thereby inhibiting RGC apoptosis. To overcome delivery limitations, farrerol-loaded bilirubin nanoparticles (FB-NPs) are developed, showing enhanced stability and neuroprotective effects in glaucomatous injury models. These findings identify the Nrf2/ferroptosis/apoptosis axis as a novel therapeutic target and present an effective nanodelivery strategy for glaucoma treatment.
✓ 已验证
产品关联
DOI
PubMed
高影响因子
MOLECULAR PHARMACEUTICS
·
2026
·Vol. 23
·期 8
·4341-4359
·
IF 4.9
Zhang Jieke,Li Yafang,Tian Chaoying,Zhang Xiaodi,Guo Jialing,Liu Chenxin,Wu Ligang,Du Bin,Cheng Genyang
Acute kidney injury (AKI) is a clinical syndrome with
high incidence
and mortality involving oxidative stress, ferroptosis, and inflammation,
yet there are no clinically effective interventions. Herein, HA@PDA@EGCG
nanoparticles were constructed using polydopamine (PDA) as carriers,
loaded with epigallocatechin gallate (EGCG) via π-π stacking,
and further surface-modified with hyaluronic acid (HA) through electrostatic
interaction. The nanoparticles had uniform morphology with a size
of approximately 50 nm and an EGCG loading capacity of 15.4 ±
0.8%. They exhibited prominent broad-spectrum antioxidant activity
and hydrogen peroxide-responsive EGCG release, with a cumulative release
rate of 58.2 ± 2.2% within 2 h and close to 80% at 12 h. Cellular
uptake and in vivo distribution confirmed the efficient CD44 receptor-mediated
internalization of the nanoparticles by human kidney-2 (HK-2) cells
as well as renal-targeted accumulation. Reactive oxygen species (ROS)
staining, mitochondrial morphology and apoptosis assays showed that
the nanoparticles effectively scavenged ROS, alleviated mitochondrial
damage, and inhibited cell apoptosis. In a cisplatin-induced in vivo
AKI model, HA@PDA@EGCG significantly restored renal function: blood
urea nitrogen and creatinine decreased to 12.3% and 27.2% of model
group levels, respectively, while alleviating renal pathological damage
and inflammation. Mechanistically, HA@PDA@EGCG inhibited ferroptosis
by downregulating acyl-CoA synthetase long-chain family member 4 (ACSL4)
to suppress lipid synthesis, chelating ferrous ions, and stabilizing
glutathione peroxidase 4 (GPX4) protein. Collectively, HA@PDA@EGCG
achieved renal protection by ameliorating oxidative stress, suppressing
inflammation and inhibiting ferroptosis through multiple pathways,
offering a novel strategy for targeted AKI therapy.
✓ 已验证
产品关联
DOI
PubMed
高影响因子
International Journal of Pharmaceutics-X
·
2026
·
IF 7.9
Yinghong Huang,Yuanyuan Zhao,Yuhong Su,Chudong He,Mengdie Mo,Weijie Zhou,Yang Lu,Fei Yu
Ferroptosis, an iron-dependent programmed cell death process driven by reactive oxygen species (ROS) accumulation, represents a promising therapeutic strategy for breast cancer. However, the efficacy of ferroptosis therapy in breast cancer is often compromised by insufficient intracellular levels of hydrogen peroxide (H 2 O 2 ) and iron ions. To address these problems, we developed pH-responsive nanoparticles comprising a metal–phenolic network (MPN) shell and a bovine serum albumin (BSA) core for the delivery of artesunate (ART) (designated as BAM NPs). The designed BAM NPs aim to amplify oxidative stress and enhance ferroptosis-based therapy for breast cancer. Upon endocytosis by tumor cells, BAM NPs underwent degradation under acidic conditions to release ART and Fe 3+ . Subsequently, the reduction of Fe 3+ to Fe 2+ by glutathione (GSH) initiated the Fenton reaction, which led to aberrant accumulation of ROS. Meanwhile, the endoperoxide bridge of ART could be cleaved by Fe 2+ to further generate carbon-centered radicals (·C). Furthermore, BAM NPs effectively deplete GSH via Fe 3+ /Fe 2+ conversion to inactivate glutathione peroxidase 4 (GPX4), thereby disrupting redox homeostasis and increasing intracellular LPO levels. Both in vitro and in vivo experiments showed that BAM NPs significantly inhibited tumor cell proliferation by inducing robust ferroptosis in tumor cells, leading to a tumor inhibition rate of 83.11%. In summary, the constructed BAM NPs served as a promising tailored nanoplatform for augmenting ferroptosis therapy in breast cancer.
✓ 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）