Advanced Healthcare Materials
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2022
·Vol. 12
·期 6
·2202150
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IF 11.092
Ying Chen,Zengqiu Yang,Sibu Wang,Qin Ma,Lingyan Li,Xingjie Wu,Qianqian Guo,Ling Tao,Xiangchun Shen
Due to the deficient catalase, abundant reduced iron and low acidic environment in lysosomes, inducing lysosomal membrane permeabilization (LMP) through Fenton reaction-based reactive oxygen species (ROS) generation recently attracts increasing attention in cancer therapy. However, the lysosomal membranes are protected by highly glycosylated membrane proteins and several endolysosomal damage-response mechanisms can rapidly repair the injured lysosomes. To produce sufficient ROS and cause complete lysosomal membranes rupture, a lysosome-targeted ROS inducer, N -(3-Aminopropyl) morpholine grafted cross-linked lipoic acid vesicles with vitamin C-loading (VC@ N3AM cLAVs), is developed. VC@ N3AM cLAVs efficiently accumulate in lysosomes and convert into two redox couples LA/DHLA (dihydrolipoic acid, reduced form of LA) and VC/DHA (dehydroascorbic acid, oxidized form of VC) by the lysosomal glutathione, which can not only produce a large amount of H 2 O 2 by pro-oxidant action but also accelerate iron transformation through the cyclic redox reactions between each other and cause the efficient conversion of the generated H 2 O 2 into highly toxic •OH. Both in vitro and in vivo experiments demonstrate that VC@ N3AM cLAVs can effectively enhance ROS production and boost LMP, finally initiation irreversible death of tumor cells via ferroptosis pathway, thus representing a potential anticancer drug for cancer therapy.
研究领域:
癌症生物学
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药学
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治疗学
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生物化学
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DOI
PubMed
高影响因子
JOURNAL OF CONTROLLED RELEASE
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2022
·
IF 11.467
Mingbo Wu,Wenwu Ling,Jiaojun Wei,Ran Liao,Haiyue Sun,Dongqiu Li,Ye Zhao,Long Zhao
As a novel non-apoptotic cell death pathway, ferroptosis can effectively enhance the antitumor effects of photodynamic therapy (PDT) by disrupting intracellular redox homeostasis. However, the reported nanocomposites that combined the PDT and ferroptosis are cumbersome to prepare, and the unfavorable tumor microenvironment also severely interferes with their tumor suppressive effects. To address this inherent barrier, this study attempted to explore photosensitizers that could activate ferroptosis pathway and found that the photosensitizer aloe-emodin (AE) could induce cellular ferroptosis based on its specific inhibiting activity to Glutathione S-transferase P1(GSTP1), a key protein for ferroptosis. Herein, we prepared [email protected] /Fe nanocrystals (NCs) with synergistic PDT and ferroptosis therapeutic effects by one-step emulsification to obtain AE NCs cores and further modification of red blood cells (RBC) membranes and ferritin. Benefiting from the involvement of ferritin, the prepared [email protected] /Fe NCs provide not only sufficient oxygen for oxygen-dependent PDT, but also Fe 3+ for iron-dependent ferroptosis in tumor cells. Furthermore, the biomimetic surface functionalization facilitated the prolonged circulation and cancer targeting of [email protected] /Fe NCs in vivo . The in vitro and in vivo results demonstrate that [email protected] /Fe NCs exhibit significantly enhanced therapeutic effects for the combined two antitumor mechanisms and provide a promising prospect for achieving PDT/ferroptosis synergistic therapy.
研究领域:
癌症治疗
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纳米技术
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药理学
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肿瘤学
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产品关联
DOI
PubMed
高影响因子
Asian Journal of Pharmaceutical Sciences
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2022
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IF 9.273
Chengcheng Wang,Jiao Wang,Xue Pan,Shuang Yu,Meiqi Chen,Yan Gao,Zilin Song,Haiyang Hu,Xiuli Zhao,Dawei Chen,Fei Han,Mingxi Qiao
As a non-apoptotic cell death form, ferroptosis offers an alternative approach to overcome cancer chemotherapy resistance. However, accumulating evidence indicates cancer cells can develop ferroptosis resistance by evolving antioxidative defense mechanisms. To address this issue, we prepared a Buthionine-(S,R)-sulfoximine (BSO) loaded metal organic framework (MOF) of BSO-MOF-HA (BMH) with the combination effect of boosting oxidative damage and inhibiting antioxidative defense. MOF nanoparticle was constructed by the photosensitizer of [4,4,4,4-(porphine-5,10,15,20-tetrayl) tetrakis (benzoic acid)] (TCPP) and the metal ion of Zr6, which was further decorated with hyaluronic acid (HA) in order to impart active targeting to CD44 receptors overexpressed cancer cells. BMH exhibited a negative charge and spherical shape with average particle size about 162.5 nm. BMH was found to restore the susceptibility of 4T1 cells to ferroptosis under irradiation. This was attributed to the combination of photodynamic therapy (PDT) and γ-glutamylcysteine synthetase inhibitor of BSO, shifting the redox balance to oxidative stress. Enhanced ferroptosis also induced the release of damage associated molecular patterns (DAMPs) to maturate dendritic cells and activated T lymphocytes, leading to superior anti-tumor performance in vivo . Taken together, our findings demonstrated that boosting oxidative damage with photosensitizer serves as an effective strategy to reverse ferroptosis resistance.
研究领域:
癌症生物学
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纳米医学
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药学
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细胞生物化学
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF CONTROLLED RELEASE
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2022
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IF 11.467
Chencheng Xue,Hui Zhang,Xuan Wang,Haoyu Du,Lu Lu,Yang Fei,Yanan Li,Yuchen Zhang,Menghuan Li,Zhong Luo
Nanotechnology-enabled ferroptosis therapy is an emerging paradigm for tumor treatment, but amplifying ferroptotic damage in tumor cells in a safe and selective manner is still challenging, which severely hinders its clinical translation. In this study, we constructed a bio-inspired protein nanocomplex based on natural-occurring bovine serum albumin (BSA) and ferritin for efficient tumor elimination via cooperatively enhanced ferroptosis therapy. The long-circulating BSA molecules provided multiple anchoring points for the efficient loading of the GPX4-inhibiting ferroptosis inducer (1S, 3R) RAS-selective lethal 3 (RSL3), which was further complexed with ferritin via acidity-responsive glutaraldehyde linkers. The ferritin moieties may not only bind to transferrin receptor 1 overexpressed on tumor cell membrane for targeted endocytic uptake but also be degraded in lysosomes to induce iron overload, which could substantially promote the lipid peroxidation in tumor cells and cooperate with the glutathione peroxidase 4 (GPX4)-inhibiting capability of RSL3 to induce pronounced ferroptosis. The in vitro and in vivo results collectively demonstrated that the albumin-ferritin-based nanocomplex could present superior antitumor effects with no obvious adverse effects, which may open new avenues for the clinical translation of ferroptosis-dependent therapeutic modalities.
研究领域:
肿瘤学
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纳米医学
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生物材料学
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产品关联
DOI
PubMed
高影响因子
Frontiers in Molecular Biosciences
·
2023
·
IF 5
Shi Hanqiang,Xiong Lie,Yan Guang,Du Shuqin,Liu Jie,Shi Yanbo
The clinical therapeutics of cervical cancer is limited due to the drug resistance and metastasis of tumor. As a novel target for antitumor therapy, ferroptosis is deemed to be more susceptible for those cancer cells with resistance to apoptosis and chemotherapy. Dihydroartemisinin (DHA), the primary active metabolites of artemisinin and its derivatives, has exhibited a variety of anticancer properties with low toxicity. However, the role of DHA and ferroptosis in cervical cancer remained unclear. Here, we showed that DHA could time-dependently and dose-dependently inhibit the proliferation of cervical cancer cells, which could be alleviated by the inhibitors of ferroptosis rather than apoptosis. Further investigation confirmed that DHA treatment initiated ferroptosis, as evidenced by the accumulation of reactive oxygen species (ROS), malondialdehyde (MDA) and liquid peroxidation (LPO) levels and simultaneously depletion of glutathione peroxidase 4 (GPX4) and glutathione (GSH). Moreover, nuclear receptor coactivator 4 (NCOA4)-mediated ferritinophagy was also induced by DHA leading to subsequent increases of intracellular labile iron pool (LIP), exacerbated the Fenton reaction resulting in excessive ROS production, and enhanced cervical cancer ferroptosis. Among them, we unexpectedly found that heme oxygenase-1 (HO-1) played an antioxidant role in DHA-induced cell death. In addition, the results of synergy analysis showed that the combination of DHA and doxorubicin (DOX) emerged a highly synergistic lethal effect for cervical cancer cells, which was related also to ferroptosis. Overall, our data revealed the molecular mechanisms that DHA triggered ferritinophagy-dependent ferroptosis and sensitized to DOX in cervical cancer, which may provide novel avenues for future therapy development.
研究领域:
肿瘤学
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药理学
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细胞生物学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
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2023
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IF 6.7
Haoze Song,Jing Liang,Yuanyuan Guo,Yang Liu,Kuiru Sa,Guohong Yan,Wen Xu,Wei Xu,Lixia Chen,Hua Li
Glutathione peroxidase 4 (GPX4) is the most promising target for inducing ferroptosis . GPX4-targeting strategies primarily focus on inhibiting its activity or adjusting its cellular level. However, small inhibitors have limitations due to the covalent reactive alkyl chloride moiety, which could lead to poor selectivity and suboptimal pharmacokinetic properties. Herein, we designed and synthesized a series of proteolysis targeting chimeras (PROTACs) by connecting RSL3, a small molecule inhibitor of GPX4, with six different ubiquitin ligase ligands. As a highly effective degrader, compound 18a is a potent degrader (DC 50, 48h = 1.68 μM, D max, 48h = 85 %). It also showed an obvious anti-proliferative effect with the IC 50 value of 2.37 ± 0.17 μM in HT1080. Mechanism research showed that compound 18a formed a ternary complex with GPX4 and cIAP and induced the degradation of GPX4 through the ubiquitin-proteasome system pathway. Furthermore, compound 18a also induced the accumulation of lipid peroxides and mitochondrial depolarization, subsequently triggering ferroptosis. Our work demonstrated the practicality and efficiency of the PROTAC strategy and offered a promising avenue for designing degraders to induce ferroptosis in cancer cells.
研究领域:
肿瘤学
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药物化学
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细胞生物学
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产品关联
DOI
PubMed
高影响因子
CHEMICO-BIOLOGICAL INTERACTIONS
·
2023
·
IF 5.1
Xi Wang,Wenjing Zhu,Miao Xing,Haiyan Zhu,Enqing Chen,Jie Zhou
Matrine (MT) is an alkaloid isolated from Sophora flavescens with various bioactivities and is widely used clinically. However, the broader its clinical use, the greater its toxicity concerns. We investigate the role of ferroptosis in MT-induced liver injury caused by an imbalance in the antioxidant pathway. Our results showed that MT could cause pathological changes in liver tissues and lead to a significant reduction in L02 cell viability. MT also reduced superoxide dismutase (SOD) and glutathione (GSH), increased malondialdehyde (MDA), reactive oxygen species (ROS), and lipid peroxidation levels, and disrupted iron homeostasis , leading to ferroptosis. In addition, MT decreased the protein levels of FTH, Nrf2 , xCT, GPX4, HO-1 and ferroptosis suppressor protein 1 (FSP1) and increased the protein levels of TRF1 and DMT1 , characteristic indicators of ferroptosis. Interestingly, the cytotoxic effects of MT were alleviated by ferroptosis inhibitor, Nrf2 agonist, or selenium supplementation. These results revealed that MT triggers hepatocyte ferroptosis by inhibiting the Nrf2/GPX4 antioxidant system.
研究领域:
药理学
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毒理学
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细胞生物学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
Journal of Materials Chemistry B
·
2025
·
IF 5.7
Lanfu Zheng,Wei Jiang,Shuming Tian,Zepeng Feng,Yanan Qi,Hongyang Fu,Liting Qi,Lianrui Chen
Photothermal therapy (PTT) represents a non-invasive therapeutic modality with considerable potential for tumor ablation. However, the complex tumor microenvironment (TME) presents substantial challenges to conventional PTT monotherapy. In this study, we developed a nanomedicine (Fe 3 O 4 @GOx@PDA) designed to synergistically eradicate tumor cells by integrating PTT with starvation therapy and ferroptosis induction. Glucose oxidase (GOx) catalyzes the oxidation of intratumoral glucose to gluconic acid and hydrogen peroxide (H 2 O 2 ). Simultaneously, the resultant H 2 O 2 facilitates intracellular Fenton-like reactions, generating reactive oxygen species (ROS) that trigger lipid peroxidation. Furthermore, Fe 2+ ions liberated within the TME react with H 2 O 2 via a Fenton-like reaction to produce abundant ROS. This ROS surge stimulates macrophage polarization towards the M1 phenotype, thereby further suppressing the proliferation and metastatic potential of colorectal cancer (CRC) cells. This multimodal therapeutic strategy, leveraging Fe 3 O 4 @GOx@PDA, demonstrates potent synergistic antitumor efficacy coupled with favorable biosafety, presenting a promising therapeutic approach for clinical colorectal cancer management.
研究领域:
纳米医学
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癌症治疗
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免疫治疗
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活性氧
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药物递送
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产品关联
DOI
PubMed
高影响因子
REDOX REPORT
·
2025
·
IF 7.4
Jingyi Ren,Ziyi Wang,Yadong Zhang,Huanting Pei,Rui Wen,Zhenao Zhang,Siqi Zhu,Xiaoya Sun,Bowen Yin,Shenghe Li,Yuxia Ma
Background: Acetaminophen (APAP) overdose is the leading cause of drug-induced acute liver failure. Sesamin (Ses), a natural polyphenolic compound, possesses diverse pharmacological properties. This study was to explore the effects of Ses on APAP-induced liver injury and the underlying molecular mechanism.Methods: In vivo, C57BL/6J mice were treated with different doses of Ses for 28 days. After overnight food deprivation, mice were intraperitoneally injected with a single dose of APAP. In vitro, the AML12 and HepG2 cells were pre-treated with Ses and then treated with APAP.Results: Ses dramatically alleviated APAP-induced hepatocellular injury in vitro and in vivo. Proteomic analysis suggested that the differentially expressed proteins were enriched in ferroptosis, autophagy, and FoxO signaling pathways between the APAP group and the Ses-treated groups. We subsequently found that ferroptosis was significantly inhibited, and autophagy was significantly enhanced in the Ses-treated group. Consistently, Ses obviously reduced the expression of Foxo1. However, hepatocyte-specific knockout Foxo1 abolished the effect of Ses on hepatocyte autophagy and ferroptosis caused by APAP in mice.Conclusions: Our findings demonstrate that Ses attenuates APAP-induced hepatotoxicity through Foxo1, which mediates both the activation of autophagy and the inhibition of ferroptosis. It provides a new strategy for the prevention and treatment of drug-induced liver injury.
研究领域:
药理学
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毒理学
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分子生物学
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肝脏病学
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF LIPID RESEARCH
·
2025
·
IF 4.1
Shaojun Pei,Wen Wang,Tingze Feng,Qiuping Wang,Yuhan Wang,Hong-Xu Liu,Xinmiao Liang,Hai-long Piao
S -palmitoylation is a dynamic and reversible post-translational modification that plays crucial roles in cancer progression. Here, we found the oncogene of metadherin (MTDH) modulates lipid metabolism and ferroptosis by its S -palmitoylation. We demonstrate that MTDH is S -palmitoylated at Cys-75 in the endoplasmic reticulum by ZDHHC1/9 and S -depalmitoylated by APT1. The flexible loop and the α-helix length in the MTDH N-terminus affect its S -palmitoylation level. In addition, metabolomics analysis found that the S -palmitoylated MTDH increases intracellular levels of triglycerides, phosphatidylethanolamines, and phosphatidylcholines. However, the non- S -palmitoylation form of MTDH-CS enhanced the interaction of between MTDH and the ferroptosis enhancer of Acyl-CoA synthetase long-chain family member 4 (ACSL4), thereby reducing ferroptosis sensitivity in breast cancer cell. Taken together, targeting MTDH S -palmitoylation may represent a novel strategy for breast cancer therapy.
研究领域:
癌症生物学
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分子生物学
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细胞生物学
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脂质代谢
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翻译后修饰
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产品关联
DOI
PubMed
高影响因子
Food & Function
·
2021
·Vol. 12
·期 24
·12671-12682
·
IF 5.396
Jing-yi Ren,Bo-wen Yin,Xiang Li,Si-qi Zhu,Jin-liang Deng,Yi-ting Sun,Zhen-ao Zhang,Zi-hao Guo,Huan-ting Pei,Fan Zhang,Rui-qiang Li,Feng-ge Chen,Yu-xia Ma
Objective: This study aimed to elucidate the pharmacological effects of sesamin (Ses) and its mechanism of action towards PM2.5-induced cardiovascular injuries. Method: Forty Sprague Dawley (SD) rats were randomly divided into five groups: a saline control group; a PM2.5 exposure group; and low-, middle-, and high-dose Ses pretreatment groups. The SD rats were pretreated with different concentrations of Ses for 21 days. Afterward, the rats were exposed to ambient PM2.5 by intratracheal instillation every other day for a total of three times. The levels of inflammatory markers, including tumor necrosis factor-alpha (TNF-α), interleukin-1beta (IL-1β), and interleukin-6 (IL-6), and indicators related to oxidative responses, such as total superoxide dismutase (SOD), reduced glutathione (GSH), glutathione peroxidase (GSH-Px), and malondialdehyde (MDA), were measured in the blood and heart. The expression of ferroptosis-related proteins in heart tissues was determined via western blot and immunohistochemistry. Results: Ses pretreatment substantially ameliorated cardiovascular injuries in rats as evidenced by the decrease in the pathological score and collagen area. The decreased levels of SOD, GSH, and GSH-Px in the heart and serum were inhibited by Ses. In addition, Ses not only notably increased the activity of antioxidant enzymes but also reduced the levels of MDA, CK, LDH, CK-MB, IL-6, TNF-α, IL-1β, and IL-6. Furthermore, Ses pretreatment upregulated the expression levels of GPX4, SLC7A11, TFRC, and FPN1 and inhibited the expression levels of FTH1 and FTL. Conclusion: Ses pretreatment could ameliorate PM2.5-induced cardiovascular injuries perhaps by inhibiting ferroptosis. Therefore, Ses pretreatment may be a novel strategy for the prevention and treatment of PM2.5-induced cardiovascular injury.
研究领域:
药理学
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心脏病学
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毒理学
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环境健康
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DOI
PubMed
高影响因子
Biomaterials Advances
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2024
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IF 5.5
Yang Liu,Pengyuan Qi,Gaojie Chen,Zhiquan Lang,Jike Wang,Xinghuan Wang
Immunotherapy is a promising mainstream approach in anti-tumor therapy. It boasts advantages such as durable responses and lower side effects. However, there are still some limitations to be addressed. Current cancer immunotherapy has shown low response rates due to inadequate immunogenicity of certain tumor cells. To address these challenges, an acid-specific nanoreactor was developed, designed to induce immunogenicity by triggering ferroptosis in tumor cells. The nanoreactor integrates glucose oxidase (GOx) with a single-atom nanoenzyme (SAE), which exhibits high peroxidase (POD)-like activity in the acidic tumor microenvironment (TME). This specific acid-sensitivity transforms endogenous hydrogen peroxide (H 2 O 2 ) into cytotoxic hydroxyl radicals (•OH). GOx enhances the POD-like SAE activity in the nanoreactor by metabolizing glucose in tumor cells, producing gluconic acid and H 2 O 2 . This nanoreactor induces high levels of oxidative stress within tumor cells through the synergistic action of SAE and GOx, leading to depletion of GSH and subsequently triggering ferroptosis. The resulting nanoreactor-induced ferroptosis leads to immunogenic cell death (ICD) and significantly recruits T lymphocyte infiltration in tumor tissues. This study was designed with the concept of triggering ferroptosis-dependent ICD mechanism in bladder cancer cells, and developed an acid-specific nanoreactor to enhance the immunotherapy efficacy for bladder cancer, which introduces a novel approach for immunotherapy of bladder cancer.
研究领域:
癌症生物学
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纳米技术
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免疫疗法
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生物医学工程
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DOI
PubMed
高影响因子
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