Nano Research
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2024
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IF 9.5
Wu Linjing,Wang Wenhao,Guo Mengqin,Fu Fangqin,Wang Wenhua,Sung Tszching,Zhang Meihong,Zhong Ziqiao,Wu Chuanbin,Pan Xin,Huang Zhengwei
Fenton reaction centered ferroptosis-apoptosis synergetic therapy has emerged as a promising tumor elimination strategy. However, the low intracellular Fenton level and accumulation of therapeutics at the lesion site greatly limit the efficacy of ferroptosis therapy. To overcome these two bottlenecks, an inhalable metal polyphenol network (MPN)-hybrid liposome, encoded as LDG, was proposed for enhancing the intracellular Fenton reaction level by co-delivering the ferroptosis inducer dihydroartemisinin (DHA) and the ferrous ion (Fe 2+ ) donor MPN. The synthesized LDG had excellent nebulization performance which significantly improved the accumulation in the lungs, about 8.2 times of intravenous injection. In terms of anticancer mechanisms, MPN raised the intracellular level of Fe 2+ by constructing iron cycling in the weakly acidic environment of tumors. Triggered by Fe 2+ , DHA with peroxide-bridge structure underwent a high level of Fenton-like reaction, promoted the production of intracellular reactive oxygen species (ROS) and induced strong ferroptosis while cooperating with apoptosis. LDG exhibited extraordinary antitumor ability in an orthotopic lung tumor model, whose tumor inhibition efficiency was 1.53 ( P = 0.0014) and 1.32 ( P = 0.0183) times of the LG group (liposomes coated with gallic acid (GA)-Fe MPN) and LD group (liposomes loaded with DHA), respectively, showing the strongest anticancer effect. In conclusion, the constructed MPN-hybrid liposomes could be a potent custom nanoplatform for pulmonary delivery and underscored the great potential of ferroptosis-apoptosis synergetic therapy.
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BIOCHEMICAL PHARMACOLOGY
·
2025
·
IF 5.6
Huisheng Zhou,Xi Zhou,Guobin Huang,Yuanyuan Zhao,Peixiang Lan,Zhishui Chen
Ischemia-reperfusion injury (IRI) and bile salt toxicity are significant contributors to post-transplant cholangiopathy. Ferroptosis appears to play a critical role in intrahepatic bile duct injury induced by ischemia–reperfusion (I/R) and bile salt toxicity. Our study aimed to elucidate the role of ferroptosis in bile duct injuries and its potential as a therapeutic target for liver diseases. Mouse models of liver ischemia–reperfusion (I/R) and α-naphthyl isocyanate (ANIT)-induced liver cholestasis were employed to investigate the role of ferroptosis in intrahepatic bile duct injury in vivo. Hypoxia-reoxygenation (H/R) and bile salt treatment models were utilized to simulate the post-transplant bile duct injury process in vitro. In mouse models of liver I/R and cholestasis, we observed a downregulation of glutathione peroxidase 4 (GPX4) and an upregulation of lipid peroxidation levels in bile duct cells. Furthermore, the ferroptosis inhibitor Liproxstatin-1 (Lip-1) significantly attenuated intrahepatic bile duct injuries. Ferroptosis inhibitors alleviated cell death and lipid peroxide accumulation in human intrahepatic biliary epithelial cells (HiBECs) subjected to H/R or glycochenodeoxycholate (GCDCA) treatment. GCDCA treatment led to ferroptosis in HiBECs along with ferritin degradation. Inhibition of autophagy alleviated GCDCA-induced bile duct cell death. Our study suggested that ferroptosis played an important role of in the intrahepatic bile duct injury during I/R or cholestasis.
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ACS Nano
·
2024
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IF 15.8
Yang Chen,Wenzhe Xu,Hao Jin,Mengsi Zhang,Shuwei Liu,Yi Liu,Hao Zhang
Heterogeneous reprogrammed nutrient metabolic networks formed by oncogenes exhibit the potential for exploring novel druggable targets and developing innovative anticancer therapeutics. Herein, based on the heterogeneous metabolic characteristics of glutamine (Gln) addiction in pancreatic cancer cells, an iron-delivery system (IDS) with enhanced endocytosis is designed for efficient ferroptosis therapy. The IDS is characterized by Gln modification and can be recognized as a source of Gln nutrients for efficient endocytic uptake by pancreatic tumor cells. Because the IDS is flexible to combine with amino acid-like components, the IDS with enhanced endocytosis is further produced by loading the Gln transporter inhibitor of V9302. V9302 is capable of suppressing molecular Gln uptake via transporter ASCT2, which generates Gln deprivation to direct metabolic reprogramming of cancer cells and enhances cellular uptake of Gln-modified IDS via RAS-stimulated macropinocytosis. The enhanced endocytosis and high iron content of IDS facilitate ferroptosis in mice pancreatic tumor models; thus, an amino acid-like ferroptosis inducer of l-buthionine sulfoximine (BSO) is further combined. The enhanced endocytosis resulting from the synergism of Gln and V9302 enables the efficient delivery of iron and BSO for ferroptosis tumor therapy. This work provides an alternative approach for enhancing intracellular drug delivery of the tumors with heterogeneous nutrient metabolism by virtue of combining nutrient-modified nanodrugs with the corresponding nutrient transporter inhibitors.
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JOURNAL OF COLLOID AND INTERFACE SCIENCE
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2024
·
IF 9.4
Wenting Li,Zhuoran Yang,Chunyu Yang,Wei Guo
This study addresses the challenge of enhancing ferroptosis efficacy for tumor therapy, particularly the limited therapeutic efficiency of current inducers due to tumor microenvironment constraints. Herein, we developed a hollow ultrasound-triggered ZnFe 2 O 4 -Bi 2 MoO 6 (ZB) S-scheme heterojunction loaded with artesunate (ART) to overcome these limitations. The ZB heterojunction with a particle size of ∼250 nm efficiently separates electron-hole pairs under ultrasound (US), promoting the generation of reactive oxygen species (ROS). The photodynamic effect of ZB further boosts ROS production, while ART, controlled-released by phase change materials under laser/US stimulation, enhances ROS production via Fe 2+ -mediated decomposition. This triple-enhanced strategy accumulates lipid peroxidation (LPO), significantly improving ferroptosis effects with a tumor suppression rate of 94.3 %. Moreover, ZB enables multimodal imaging and stimulates antitumor immunity, demonstrating its potential as a diagnostic and therapeutic agent. Our findings demonstrate the potential of this ZB@ART system in advancing ferroptosis-based tumor therapies, inspiring future designs of efficient ferroptosis inducers.
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Scientific Reports
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2024
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IF 3.8
Si-Chun Gu,Zhi-Guo Xie,Min-Jue Gu,Chang-De Wang,Li-Min Xu,Chen Gao,Xiao-Lei Yuan,You Wu,Yu-Qing Hu,Yang Cao,Qing Ye
Ferroptosis is an iron-dependent cell death form characterized by reactive oxygen species (ROS) overgeneration and lipid peroxidation. Myricetin, a flavonoid that exists in numerous plants, exhibits potent antioxidant capacity. Given that iron accumulation and ROS-provoked dopaminergic neuron death are the two main pathological hallmarks of Parkinson’s disease (PD), we aimed to investigate whether myricetin decreases neuronal death through suppressing ferroptosis. The PD models were established by intraperitoneally injecting 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) into rats and by treating SH-SY5Y cells with 1-methyl-4-phenylpyridinium (MPP + ), respectively. Ferroptosis was identified by assessing the levels of Fe 2+ , ROS, malondialdehyde (MDA), and glutathione (GSH). The results demonstrated that myricetin treatment effectively mitigated MPTP-triggered motor impairment, dopamine neuronal death, and α-synuclein (α-Syn) accumulation in PD models. Myricetin also alleviated MPTP-induced ferroptosis, as evidenced by decreased levels of Fe 2+ , ROS, and MDA and increased levels of GSH in the substantia nigra (SN) and serum in PD models. All these changes were reversed by erastin, a ferroptosis activator. In vitro, myricetin treatment restored SH-SY5Y cell viability and alleviated MPP + -induced SH-SY5Y cell ferroptosis. Mechanistically, myricetin accelerated nuclear translocation of nuclear factor E2-related factor 2 (Nrf2) and subsequent glutathione peroxidase 4 (Gpx4) expression in MPP + -treated SH-SY5Y cells, two critical inhibitors of ferroptosis. Collectively, these data demonstrate that myricetin may be a potential agent for decreasing dopaminergic neuron death by inhibiting ferroptosis in PD.
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Cell Communication and Signaling
·
2024
·Vol. 22
·期 1
·1-20
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IF 8.2
Guo Junchen,Wang Shanjie,Wan Xin,Liu Xiaoxuan,Wang Zeng,Liang Chenchen,Zhang Zhenming,Wang Ye,Yan Miao,Wu Pengyan,Fang Shaohong,Yu Bo
Ferroptosis is a regulatory cell death process pivotal in myocardial ischemia–reperfusion (I/R) injury. However, the precise mechanism underlying myocardial ferroptosis remains less known. In this study, we investigated the pathophysiological mechanisms of methylmalonic acid (MMA) associated with ferroptosis activation in cardiomyocytes after I/R. We found an increase level of MMA in patients with acute myocardial injury after reperfusion and AC16 cells under hypoxia/reoxygenation (H/R) condition. MMA treatment was found to be associated with excessive oxidative stress in cardiomyocytes, leading to ferroptosis-related myocardial injury. In mice with I/R injury, MMA treatment aggravated myocardial oxidative stress and ferroptosis, which amplified the myocardial infarct size and cardiac dysfunction. Mechanistically, MMA promoted NOX2/4 expression to increase reactive oxygen species (ROS) production in cardiomyocytes, aggravating myocardial injury. Notably, the increased ROS further activated ferroptosis by inhibiting solute carrier family 7 member 11 (SLC7A11) and glutathione peroxidase 4 (GPX4) expression. In addition, MMA decreased the ectopic nuclear distribution of nuclear factor E2-related factor 2 (NRF2) by increasing the interaction between NRF2 and kelch-like ECH-associated protein 1 (KEAP1). This impeded the activation of GPX4/SLC7A11, downstream of NRF2, activating ferroptosis and aggravating myocardial cell injury. Collectively, our study indicates that MMA activates oxidative stress and ROS generation, which induces ferroptosis to exacerbate cardiomyocyte injury in an I/R model. These findings may provide a new perspective for the clinical treatment of I/R injury and warrant further investigation.
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CHEMICAL ENGINEERING JOURNAL
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2024
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IF 13.3
Lei Xu,Jiahe Hu,Xiuwei Yan,Hongtao Zhao,Mo Geng,Jiheng Zhang,Chunxiao Zhou,Zhihui Liu,Bo Li,Shaoshan Hu
Photodynamic therapy (PDT) is an effective treatment for glioblastoma (GBM) that activates photosensitizers to produce reactive oxygen species (ROS) while minimizing harm to normal tissues. However, the therapeutic outcomes of PDT are often unsatisfactory. This limitation arises partly from the challenges posed by the blood–brain barrier (BBB) in transporting photosensitizers and partly from the excessive levels of glutathione (GSH) in the tumor microenvironment (TME), which can neutralize ROS. Hypericin (HYP) has emerged as a promising photosensitizer for PDT due to its excellent photosensitizing properties and antitumor activity. Dysregulated iron metabolism is a hallmark of numerous cancers, including GBM. In this study, biodegradable tetra-sulfide-bound dendritic mesoporous organosilicas nanocomposite (NCs) modified with bovine serum albumin (BSA) were synthesized. NCs penetrates the BBB and selectively targets GBM by binding to secreted acidic protein acidic and rich in cysteine (SPARC), an albumin-binding receptor that is prominently expressed in both the BBB and GBM. Upon degradation in response to high GSH concentrations in the TME, the NCs release their payload while concurrently depleting GSH. Under laser irradiation, the ROS-generating agent HYP, loaded within the NCs, is combined with the ferroptosis inducer erastin to achieve a synergistic anti-GBM effect via PDT/ferroptosis. Additionally, the NCs induces oxeiptosis by regulating KEAP1/PGAM5/AIFM1 pathway. Consequently, NC inhibits GBM growth by inducing ferroptosis and oxeiptosis through excessive ROS production. This study demonstrates the potential of NCs to enhance the effectiveness of PDT, offering a promising therapeutic strategy for GBM patients.
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CHEMICAL ENGINEERING JOURNAL
·
2024
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IF 13.3
Ji Liu,Mengjuan Sun,Zhen Li,Hongguang Xiang,Qiyue Wang,Xiaofei Xin,Yan Shen
Glioblastoma, the most common malignant brain tumor with a poor prognosis, still needs to develop effective therapeutic strategies to prolong the patient’s survival. Inducing GBM tumor cell ferroptosis could be the specific assay to improve GBM therapeutic efficiency. In comparison, ferroptosis in GBM cells is limited by the low intracellular ferrous ion concentration and oxidation resistance. Herein, an MNP-based ferroptosis catalytic nanoreactor loading cisplatin (CMNP-Cis-Arg) was designed to evaluate their targeted delivery and therapeutic efficiency in GBM treatment. The ferroptosis catalytic nanoreactors achieved an effective GBM targeted transportation via chitosan oligosaccharide driven GLUT1-mediated BBB permeabilization and arginine-based tumor chemotactic. CMNP-Cis-Arg improves synergistically lipid oxidation in GBM cells by inducing ROS generation and depleting intracellular GSH. The MNPs elevate ROS levels in tumor cells by enhancing Fe 2+ -based Fenton reaction and the encapsulated cisplatin as a chemotherapy agent depleting GSH via inducing the DNA strand broken. Moreover, the CMNP-Cis-Arg further induces NO biosynthesis and generates ONOO – with high oxidability to increase lipid oxidation. The anti-GBM ability of the CMNP-Cis-Arg was evaluated both in vitro and in vivo, significantly inducing the GBM tumor cells’ apoptosis and reducing the tumor burden in an orthotopic mouse model. The investigation provided a novel ferroptosis catalytic nanoreactor and confirmed their anti-GBM efficiency in boosting tumor intracellular ferroptosis, suggesting a potential therapeutic strategy worth further investigating preclinically.
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ACS Applied Nano Materials
·
2025
·
IF 5.5
Lekang Liu,Mingbo Shao,Luoyuan Guo,Wenjun Wang,Xiuwen Zheng,Xiaolei Jiang
We have developed an innovative Cu-doped and DTX-loaded Cu-MnO2@DTX@FA (MCDF) nanodrug designed to strategically alter tumor microenvironment (TME) by harnessing the synergistic effects of chemodynamic therapy (CDT), chemotherapeutic agents, and the induction of ferroptosis and cuproptosis. The MCDF nanodrug efficiently degrades, releasing abundant Mn4+, Cu2+, and DTX. The conversion of Cu2+ to Cu+ facilitated by FDX1 initiates cuproptosis, while, similar to Mn2+, Cu+ reacts with hydrogen peroxide (H2O2) to generate hydroxyl radicals (·OH). Cu2+ and Mn4+ oxidize glutathione (GSH), significantly depleting GSH levels in tumor cells and inactivating GPX4, which further promotes ferroptosis. The release of Cu2+ and Mn4+ intensifies the cuproptosis. DTX effectively disrupts the cell division cycle, thereby inhibiting the proliferation and spread of tumor cells. The FA-modified MCDF is designed to evade immune detection while selectively targeting tumor tissues, ensuring precision in treatment delivery. This cutting-edge material not only provides a multifunctional therapeutic strategy but also sets the stage for the next generation of tumor-targeting nanomedicines.
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Journal of Inflammation Research
·
2025
·
IF 4.1
Yi-Xuan Zeng,Ni-Ren Li,Bing-Ying Deng,Yu-Feng Gu,Si-Fan Lu,Yi Liu
Background Ulcerative colitis is a chronic intestinal disease linked to intestinal barrier damage, ferroptosis and dysbiosis. Coix lacryma-jobi is a natural food with food-medicine homology, whose seed-derived oil (Coix seed oil, CSO) has been shown anti-inflammatory activity in vitro. Here, the effects and mechanisms of CSO on ulcerative colitis (UC) in vivo are systematically investigated.Methods Firstly, the UC mice was replicated by 3% DSS, and assessed the efficacy of CSO by observing the fecal occult blood, colon length, DAI score and pathological histomorphological changes of colon tissues. The anti-inflammatory and barrier-protective effects of CSO were observed by AB staining and qRT-PCR. Secondly, the biological targets of CSO were obtained from TCMSP database and Swiss Target Prediction database, ferroptosis targets were downloaded from FerrDb platform, and UC-related disease targets were obtained from GEO database, and the intersection of the above three was taken to obtain “CSO-UC-Ferroptosis” intersection targets, which were analysed by GO and KEGG enrichment, GSEA analysis, and immune cell infiltration and validation. Finally, the core genes of “CSO-UC-Ferroptosis” were molecular docking with the potential active components of CSO. In order to further verify the effect of CSO on ferroptosis, the GPX4 agonist RSL-3 was used to stimulate mice in vivo, and the levels of Iron, MDA and SOD were measured, and immunohistochemistry was used to detect the effects of tight junction proteins and the “CSO-UC-Ferroptosis” core protein in mice. Besides, the effect of CSO was further evaluated by observing the intercellular junctions of the colon tissues of each group under electron microscope. In addition, 16sRNA sequencing was performed on the intestinal contents of the mice to observe the effects of CSO on the intestinal flora of UC mice.Results CSO improved physiological parameters, reduced inflammation response and intestinal barrier damage, regulated ferroptosis, and restored gut microbiota balance in UC mice. Bioinformatics results showed that G6PD, ABCC1 were core targets at the intersection of CSO, UC and ferroptosis, which also demonstrated the similar expression of the core genes in DSS-induced UC mice models in vivo.Conclusion Our findings demonstrate for the first time that CSO ameliorated UC by regulating intestinal barrier damage, ferroptosis and the gut microbiota in DSS-induced mice, suggesting that CSO as a promising candidate for UC treatment and warranting further investigation.
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INTERNATIONAL IMMUNOPHARMACOLOGY
·
2024
·
IF 4.8
Chenlu Huo,Shuang Li,Anting Liu,Yujie Hong,Yan Zhu
It has been reported that the symptoms of rheumatoid arthritis (RA) can be ameliorated by acupuncture, an external treatment of traditional Chinese medicine. However, the immune mechanism underlying its action is elusive. Accordingly, this study investigated the role and mechanism of manual acupuncture (MA) in collagen-induced arthritis (CIA) in mice. The results demonstrated that MA or NaB treatment reduced Articular Index scores and right paw thickness and alleviated synovial inflammation and cartilage damage. MA or NaB treatment altered the content and relative abundance of short-chain fatty acids, particularly butyric and propionic acids, in feces. Additionally, MA or NaB treatment elevated SCD1, SREBP1, and GPX4 protein expression in synovial tissues and GSH-px contents in serum while decreasing ROS fluorescence intensity and MDA contents in peripheral blood. A linear correlation was found between the relative expression of SCD1 and SREBP1 in synovial tissues and the contents of propionic acids and butyric acids in feces, as well as between the contents of propionic acids and butyric acids. In summary, MA regulates butyric acids to inhibit ferroptosis, therefore suppressing inflammation in RA.
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BIOMATERIALS
·
2024
·
IF 12.8
Huan Wang,Xinchen Liu,Xiangyu Yan,Yong Du,Fang Pu,Jinsong Ren,Xiaogang Qu
Anticancer nanomedicines used for ferroptosis therapy generally rely on the direct delivery of Fenton catalysts to drive lipid peroxidation in cancer cells. However, the therapeutic efficacy is limited by the ferroptosis resistance caused by the intracellular anti-ferroptotic signals. Herein, we report the intrinsic ATPase-mimicking activity of a vanadium carbide MXene nanozyme (PVCMs) to pharmacologically modulate the nuclear factor erythroid 2-related factor 2 (Nrf2) program, which is the master anti-ferroptotic mediator in the ironclad defense system in triple-negative breast cancer (TNBC) cells. The PVCMs perform high ATPase-like activity that can effectively and selectively catalyze the dephosphorylation of ATP to generate ADP. Through a cascade mechanism initiated by falling energy status, PVCMs can powerfully hinder the Nrf2 program to selectively drive ferroptosis in TNBC cells in response to PVCMs-induced glutathione depletion. This study provides a paradigm for the use of pharmacologically active nanozymes to moderate specific cellular signals and elicit desirable pharmacological activities for therapeutic applications.
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