BIOMATERIALS
·
2023
·
IF 14
Ping Huang,Yao Yang,Wenyan Wang,Zimu Li,Nansha Gao,Hongzhong Chen,Xiaowei Zeng
Insufficient immune stimulation and stubborn immune resistance are the critical factors limiting tumor immunotherapy. Here, we report a multifunctional nanoprodrug platform with self-driven indoximod (IND) release and oxidative stress amplification. The aim is to awaken immune responses and block the indoleamine 2,3-dioxygenase (IDO) pathway through a combination of ferroptosis , photothermal therapy, and immunotherapy. This nanosystem improved the delivery efficiency of IND due to click chemistry linked ROS responsive prodrug and self-driven drug release. Meanwhile, the tactic of simultaneously increasing ROS and eliminating GSH amplified oxidative stress and strengthened ferroptosis, which further enhanced immunogenicity along with polydopamine-based photothermal therapy. IDO immunization combined with ferroptosis as well as photothermal therapy not only stimulated immune response, but also reversed immune suppression with enhanced immune memory . Therefore, primary tumor, distant tumor, and cancer metastasis were inhibited. This study provides a perspective on immunotherapeutics for cancer treatment.
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Biomaterials Science
·
2022
·Vol. 11
·期 2
·518-532
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IF 7.59
Siyu Ma,Xiao Liang,Ning Yang,Jie Yang,Jun Zhang,Xiuhua Pan,Yawen Wei,Zengyi Liu,Qi Shen
Until now, treatment of refractory tumors and uncontrolled metastasis by cancer immunotherapy has not yet achieved satisfactory therapeutic results due to the insufficient in vivo immune response. Here, we proposed the construction of a therapeutic cancer nanovaccine Fe@OVA-IR820 with ferroptosis-inducing and photothermal properties for boosting cancer immunotherapy. Fe3+ ions were chelated inside the exogenous antigen ovalbumin (OVA) by biomineralization to form the nanovaccine, to which the photosensitizer IR820 was loaded by electrostatic incorporation. After intratumoral injection, in situ immunogenic cell death (ICD) was triggered as a result of Fe3+-dependent ferroptosis. Endogenous neoantigens and damage-associated molecular patterns (DAMPs) were released because of ICD and worked synergically with the exogenous OVA to provoke the immune response, which was further amplified by the photothermal effect after near-infrared irradiation. The enhanced recruitment and infiltration of T cells were observed and resulted in the suppression of the primary tumor. The therapeutic regiment that combined Fe@OVA-IR820 nanovaccine with cytotoxic T lymphocyte-associated protein 4 (CTLA-4) checkpoint blockade significantly boosted anti-cancer immunity and inhibited the growth of distal simulated metastases. Therefore, we proposed Fe@OVA-IR820 nanovaccine combined checkpoint blockade as a potential therapeutic strategy for melanoma treatment.
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SCIENCE OF THE TOTAL ENVIRONMENT
·
2022
·
IF 10.753
Yingxia Hu,Haijie Wu,Chenying Lu,Hanqing Xu,Boyang Li,Wanchun Guan,Mingjiang Wu,Yitian Gao,Haibin Tong
Cadmium (Cd) is a widely distributed toxic heavy metal that enters the environment via anthropogenic mobilization and accumulates in plants and animals, causing metabolic abnormalities even mortality. Although the toxic effects and stress damage of cadmium have been investigated extensively over the past few decades, research on its ability to trigger ferroptosis, growth retardation, and behavioral abnormalities is insufficient. As a result, the effects of CdCl 2 exposure on growth and development, activity and sleep, and ferroptosis in this study were examined in fruit fly ( Drosophila melanogaster ). When exposed to 0.5 mM CdCl 2 , the entire growth period from larvae to adults was prolonged, and the rates of pupation and eclosion were decreased. Additionally, CdCl 2 exposure resulted in a decrease in body weight and individual size of fruit fly and high lethality rate. Moreover, CdCl 2 exposure altered fruit fly behavior, including decreased activity and increased sleep duration, particularly in females. Ferrostatin-1 (Fer-1) is a potent selective ferroptosis inhibitor that effectively slows lipid hydroperoxide accumulation to rescue body size reduction and restore activity and sleep in CdCl 2 -exposed female flies. CdCl 2 exposure could induce ferroptosis in fruit fly mechanistically, as evidenced by inhibition of Nrf2 signaling pathway, accumulation of lipid peroxidation, impairment of GPX4 antioxidant system, and upregulation of iron metabolism. Our findings suggest that Cd exposure triggers ferroptosis, which leads to growth retardation and behavioral disorders in fruit fly.
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Bioactive Materials
·
2022
·
IF 16.874
Chang Liu,Quan Zou,Huixin Tang,Jia Liu,Shiqi Zhang,Caihong Fan,Junwei Zhang,Ruiqing Liu,Yashan Liu,Ruiyan Liu,Yan Zhao,Qiang Wu,Zhi Qi,Yanna Shen
Myocardial injury as one of the severe complications leads to the increasing morbidity and mortality in patients with sepsis. Recent studies reported that reactive oxygen species (ROS)-mediated ferroptosis plays a critical role in the development of heart diseases. Therefore, we hypothesized that anti-ferroptosis agent might be a novel potential therapeutic strategy for sepsis-induced cardiac injury. Herein, we demonstrated that a small biocompatible and MRI-visible melanin nanoparticles (MMPP) improves myocardial function by inhibiting ROS-related ferroptosis signaling pathway. In LPS-induced murine sepsis model, after a single dose intravenously injection of MMPP treatment, MMPP markedly alleviated the myocardial injury including cardiac function and heart structure disorder through suppressing iron-accumulation induced ferroptosis. In vitro , MMPP inhibited cardiomyocyte death by attenuating oxidative stress, inflammation and maintaining mitochondrial homeostasis. Collectively, our findings demonstrated that MMPP protected heart against sepsis-induced myocardial injury via inhibiting ferroptosis and inflammation, which might be a novel therapeutic approach in future.
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Cell Death & Disease
·
2022
·Vol. 13
·期 11
·1-12
·
IF 9.685
Hu Xiaomeng,He Yuchao,Han Zhiqiang,Liu Wei,Liu Dongming,Zhang Xihao,Chen Lu,Qi Lisha,Chen Liwei,Luo Yi,Li Qiang,Chen Peng,Wu Qiang,Zhu Xiaolin,Guo Hua
Effective strategies for hepatocellular carcinoma, which is the second leading cause of death worldwide, remain limited. A growing body of emerging evidence suggests that ferroptosis activation is a novel promising approach for the treatment of this malignancy. Nevertheless, the potential therapeutic targets and molecular mechanisms of ferroptosis remain elusive. In this study, we found that PNO1 is a bona fide inhibitor of ferroptosis and that autophagy induced by PNO1 promotes cystine/glutamate antiporter SLC7A11 while increasing the synthesis and accumulation of intracellular glutamate. This increase is followed by an equally proportional addition in cystine uptake, which consequently enhances system Xc - activity that leads to the inhibition of ferroptosis. In the maintenance of redox homeostasis, system Xc - activated via PNO1-autophagy metabolism is responsible for maintaining cysteine for glutathione (GSH) synthesis, and the final GSH metabolic reprogramming protects HCC cells from ferroptosis. The combination of PNO1 inhibition with drugs causing ferroptosis induction, particularly sorafenib, the first-line drug associated with ferroptosis in liver cancer shows therapeutic promise in vitro and in vivo. Together, our findings indicated that PNO1 protects HCC cells from ferroptotic death through autophagy-mediated GSH metabolic remodeling, and we identified a candidate therapeutic target that may potentiate the effect of ferroptosis-based antitumor therapy.
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iScience
·
2022
·
IF 6.107
Kun Fang,Sha Du,Dachuan Shen,Zhipeng Xiong,Ke Jiang,Dapeng Liang,Jianxin Wang,Huizhe Xu,Lulu Hu,Xingyue Zhai,Yuting Jiang,Zhiyu Xia,Chunrui Xie,Di Jin,Wei Cheng,Songshu Meng,Yifei Wang
Summary Ferroptosis is a new kind of regulated cell death that is characterized by highly iron-dependent lipid peroxidation. Cancer cells differ in their sensitivity to ferroptosis. Here we showed that the Suppressor of fused homolog (SUFU), a critical component in Hedgehog signaling, regulates ferroptosis sensitivity of breast cancer cells. Ectopic SUFU expression suppressed, whereas depletion of SUFU enhanced the sensitivity of breast cancer cells to RSL3-triggered ferroptosis through deregulation of ACSL4. Moreover, SUFU depletion promoted the activation of Yes-associated protein (YAP), thereby increasing the expression of ACSL4. Mechanistically, SUFU is associated with LATS1. Deletion of a region comprising residues 174–385 in SUFU disrupted SUFU binding to LATS1, thus abrogating SUFU-mediated downregulation of the YAP-ACSL4 axis and sensitivity to ferroptosis. Noteworthy, we showed that vincristine downregulated SUFU, thus increasing breast cancer cell sensitivity to RSL3 in vitro and in vivo . Together, our findings uncover SUFU as a novel regulator in ferroptosis sensitivity.
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BIOMATERIALS
·
2022
·
IF 15.304
Zhifang Li,Chunmei Wang,Chen Dai,Ruizhi Hu,Li Ding,Wei Feng,Hui Huang,Yin Wang,Jianwen Bai,Yu Chen
Chemodynamic therapy represents a distinct anti-tumor strategy by activating intratumoral chemical catalytic reactions to produce highly toxic reactive oxygen species (ROS) from non-/limited-toxic nanocatalysts . However, the low efficacy of ROS generation still remains a major challenge for further clinical translation. Herein, a liposomal nanosystem which simultaneously encapsulated copper peroxide nanodots (CPNs) and artemisinin (ART) was constructed for autophagy-enhanced and ferroptosis-involved cancer cell death owing to Cu-based dual catalytic strategy. To be specific, the CPN components, served as a H 2 O 2 self-supplying platform, release H 2 O 2 and Cu 2+ under acidic tumor environment and endogenously generate . OH via Fenton-like reaction (catalytic reaction I). In addition, Cu 2+ species catalyze ART components to produce ROS radicals (catalytic reaction II), further augmenting the intracellular oxidative damage and lipid peroxide accumulation, leading to cancer cell death. Specifically, ART also acted as a potent autophagy inducer increasing the level of intracellular iron pool through degradation of ferritin , which could promote cancer cell ferroptosis , producing the best antineoplastic effect. After accumulation into the tumor sites, ultrasound irradiation was applied to trigger the release of CPNs and ART from liposomal nanosystems, and amplify the efficacy of catalytic reaction for maximum therapeutic effect. Both in vitro and in vivo therapeutic outcomes suggest the outstanding autophagy-augmented ferroptosis-involved cancer-therapeutic efficacy, which was further corroborated by transcriptome sequencing. In this work, Cu was firstly proven to trigger ART to produce ROS species, but also provide a TME-responsive nanoplatform for potentially suppressing tumor growth by autophagy-augmented ferroptosis-involved cancer nanotherapy.
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NEUROTOXICITY RESEARCH
·
2022
·Vol. 40
·期 2
·596-604
·
IF 3.978
Wang Fei,Li Wu-lin,Shen Li-juan,Jiang Ting-ting,Xia Jian-jun,You Da-li,Hu Shan-you,Wang Li,Wu Xiao
Intracerebral hemorrhage (ICH) is the deadliest type of stroke. Oxidative stress was considered to play an important role in ICH-induced secondary injury. Crocin, the main compound isolated from Crocus sativus L., possesses a potential anti-oxidative function in many types of diseases including ICH. In the current study, the protective role of crocin in ICH-induced brain injury was investigated in the ICH model. The ICH-induced brain edema and neurological deficits were analyzed by brain edema measurement and neurological testing. The superoxide dismutase (SOD) and glutathione peroxidase (GSH-px) activity and the content of malondialdehyde (MDA) were assessed by a total superoxide dismutase assay kit. The expressions of ferroptosis-related genes were verified by quantitative real-time PCR (qPCR) and western blotting. The ICH-induced brain edema and neurological deficits were significantly decreased after treatment with crocin. Moreover, the SOD and GSH-px activities were obviously increased in the ICH with crocin-treated group compared with the ICH group, while the content of MDA was markedly decreased after treatment with crocin. Crocin inhibited ferroptosis of neuron cells, as evidenced by increased Fe 2+ concentration and the expression of GPX4, FTH1, and SLC7A11. Mechanistically, crocin treatment increased the expression and nuclear translocation of Nrf2. Our data suggest that crocin alleviates intracerebral hemorrhage–induced neuronal ferroptosis by facilitating Nrf2 nuclear translocation.
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ENVIRONMENTAL TOXICOLOGY
·
2022
·Vol. 37
·期 9
·2201-2213
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IF 4.109
Qi Xiong,Xiang Tian,Congyue Xu,Baomiao Ma,Wei Liu,Binlian Sun,Qin Ru,Xiji Shu
PM 2.5 exposure has been demonstrated to correlate with neurological disorders recently. Ferroptosis is recognized as a newly found programmed form of cell death associated with neurodegenerative diseases, while glutathione peroxidase 4 (GPX4) is a key regulator of ferroptosis. However, the relationship between PM 2.5 -induced neurotoxicity and ferroptosis is still unclear. The current study aims to investigate if ferroptosis is involved in neurotoxicity post PM 2.5 exposure and its underlying mechanism. The PM 2.5 -treated neuronal Neuro-2a (N2A) and SH-SY5Y cells were applied to the current study. The results showed that PM 2.5 significantly increased the neuronal cell death, yet the ferroptosis antagonist Ferrostain-1 (Fer-1) markedly decreased the cell death induced by PM 2.5 . Western blot further confirmed that ferroptosis was triggered post PM 2.5 treatment in N2A cells by decreasing expressions of GPX4 and ferritin heavy chain (FTH), as well as enhancing expressions of ferritin light chain (FTL) and transferrin receptor protein (TFRC). Meanwhile, PM 2.5 treatment augmented neuronal oxidative damage and mitochondrial dysfunction. The bioinformatic analysis indicated that CREB could be the regulator of GPX4, and our results showed that ERK/CREB pathway was down-regulated in N2A cells post PM 2.5 treatment. The addition of ERK1/2 agonist post PM 2.5 treatment significantly inhibit ferroptosis via increasing the expression of GPX4. Taken together, the present study demonstrated that PM 2.5 -induced ferroptosis via inhibiting ERK/CREB pathway, and these findings will advance our knowledge of PM 2.5 -induced cytotoxicity in the nervous system.
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Bioactive Materials
·
2021
·
IF 14.593
Haibao Peng,Xingcai Zhang,Peng Yang,Jiaxu Zhao,Wei Zhang,Nianping Feng,Wuli Yang,Jing Tang
The emergence of multidrug treatment resistance presents a hurdle for the successful chemotherapy of tumours. Ferroptosis, resulting from the iron-dependent accumulation of lipid peroxides, has the potential to reverse multidrug resistance. However, simultaneous delivery of the iron sources, ferroptosis inducers, drugs, and enhanced circulation carriers within matrices remains a significant challenge. Herein, we designed and fabricated a defect self-assembly of metal-organic framework (MOF)-red blood cell (RBC) membrane-camouflaged multi-drug-delivery nanoplatform for combined ferroptosis-apoptosis treatment of multidrug-resistant cancer. Ferroptosis and chemotherapeutic drugs are embedded in the centre of the iron (III)-based MOF at defect sites by coordination with metal clusters during a one-pot solvothermal synthesis process. The RBC membrane could camouflage the nanoplatform for longer circulation. Our results demonstrate that this defect self-assembly-enabled MOF-membrane-camouflaged nanoplatform could deplete the glutathione, amplify the reactive oxidative species oxidative stress, and enable remarkable anticancer properties. Our work provides an alternative strategy for overcoming multidrug resistance, which could regulate the fluidity and permeability of the cell membrane by ferroptosis to downregulate of P -glycoprotein protein expression by ferroptosis. This defect self-assembly-enabled MOF-membrane-camouflaged multi-drug-delivery nanoplatform has great therapeutic potential.
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Asian Journal of Pharmaceutical Sciences
·
2023
·
IF 10.2
Yong Huang,Yi Lin,Bowen Li,Fu Zhang,Chenyue Zhan,Xin Xie,Zhuo Yao,Chongzhi Wu,Yuan Ping,Jianliang Shen
Ferroptosis has emerged as a potent form of no-apoptotic cell death that offers a promising alternative to avoid the chemoresistance of apoptotic pathways and serves as a vulnerability of cancer. Herein, we have constructed a biomimetic self-assembly nano-prodrug system that enables the co-delivery of gefitinib (Gefi), ferrocene (Fc) and dihydroartemisinin (DHA) for the combined therapy of both ferroptosis and apoptosis. In the tumor microenvironment, this nano-prodrug is able to disassemble and trigger drug release under high levels of GSH. Interestingly, the released DHA can downregulate GPX4 level for the enhancement of intracellular ferroptosis from Fc, further executing tumor cell death with concomitant chemotherapy by Gefi. More importantly, this nano-prodrug provides highly homologous targeting ability by coating related cell membranes and exhibits outstanding inhibition of tumor growth and metastasis, as well as no noticeable side-effects during treatments. This simple small molecular self-assembled nano-prodrug provides a new reasonably designed modality for ferroptosis-combined chemotherapy.
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Acta Biomaterialia
·
2023
·
IF 9.7
Xinyu Zhang,Xueli Xu,Huimin Liu,Nengyi Ni,Shuangqing Liu,Yufang Gong,Guiqi Ma,Linlin Song,Qingwei Meng,Qing Fan,Xiao Sun
Ferroptosis-based nanoplatforms have shown great potential in cancer therapy. However, they also face issues such as degradation and metabolism. Carrier-free nanoplatforms consisting of active drugs can effectively avoid the security issues associated with additional carrier ingredients. Herein, a biomimetic carrier-free nanoplatform ( [email protected] ) was designed to treat cancer by modulating cascade metabolic pathways of ferroptosis. CCR2-overexpressing macrophage membrane-modified HESN can target cancer cells via the CCR2-CCL2 axis. The acidic tumor microenvironment (TME) can disrupt the supramolecular interaction of HESN, releasing hemin and erastin. Then, erastin could induce cancer cells ferroptosis by inhibiting system X C − pathways, while hemin, a vital component of blood to transport oxygen, could be broken down by heme oxygenase-1 (HO-1), increasing the intracellular Fe 2+ concentration to induce cancer cells' ferroptosis further. Meanwhile, erastin could enhance the activity of HO-1, further promoting the release of Fe 2+ from hemin. As a result, [email protected] demonstrated superior therapeutic efficacy in both primary and metastatic tumors in vitro and in vivo . The carrier-free [email protected] provided cascade ferroptosis tumor therapy strategies for potential clinical application. Statement of significance CCR2-overexpressing biomimetic carrier-free nanoplatform ( [email protected] ) was designed for cancer treatment by modulating metabolic pathways of ferroptosis. HESN modified with CCR2-overexpressing macrophage membrane can target tumor cells via the CCR2-CCL2 axis. HESN was composed of hemin and erastin without additional vectors. Erastin could directly induce ferroptosis, while hemin could be broken down by heme oxygenase-1 (HO-1), increasing the intracellular Fe 2+ concentration to enhance ferroptosis further. Meanwhile, erastin could improve the activity of HO-1, promoting the release of Fe 2+ from hemin. Therefore, [email protected] with good bioavailability, stability, and simple preparation can realize cascade ferroptosis tumor therapy and have the potential prospect of clinical translation.
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