ADVANCED MATERIALS
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2024
·
IF 27.4
Rui Wang,Weimin Nie,Xin Yan,Kuankuan Luo,Qi Zhang,Tao Wang,Enhao Lu,Yiting Chen,Yu Luo,Zhiwen Zhang,He Wang,Jing Zhao,Xianyi Sha
Nerve injury represents the primary reason of mortality and disability in ischemic stroke, but effective drug delivery to the region of cerebral ischemia and hypoxia poses a significant challenge in neuroprotective treatment. To address these clinical challenges, a biomimetic nanomotor, Pt@LF is designed, to facilitate deep delivery of neuroprotective agents and inhibit ferroptosis in ischemic stroke. Pt@LF traverses the blood-brain barrier (BBB) and penetrates into deep cerebral ischemic-hypoxic areas due to the active targeting capacity of apo-lactoferrin (Apo-LF) and the self-propelling motion properties of nanomotors. Subsequently, Pt@LF loosens thrombus and alleviates the “no reflow” phenomenon via mechanical thrombolysis. Thanks to the various enzyme-like abilities and multi-target ferroptosis inhibition capability, Pt@LF ameliorates the inflammatory microenvironment and rescues dying neurons. In conclusion, Pt@LF demonstrates efficiently deep penetration and neuroprotective effects in vitro and vivo. And this study provides a promising therapeutic platform for the treatment of ischemic stroke.
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EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
·
2024
·
IF 6
Huiyan Hu,Fan Zhang,Zhujun Sheng,Shuang Tian,Gechang Li,Shuanghui Tang,Yajie Niu,Jiawan Yang,Yunjun Liu
This paper introduces a new ligand, 4,6-dichloro-5-(1 H -imidazo [4,5-f]phenanthroline-2-yl)pyrimidin-2-amine (DPPA), and its corresponding new iridium(III) complexes: [Ir(ppy) 2 (DPPA)](PF 6 ) (2a) (where ppy represents deprotonated 2-phenylpyridine), [Ir(bzq) 2 (DPPA)](PF 6 ) (2b) (with bzq indicating deprotonated benzo[h]quinoline), and [Ir(piq) 2 (DPPA)](PF 6 ) (2c) (piq denoting deprotonated 1-phenylisoquinoline). The cytotoxic effects of both DPPA and 2a, 2b, and 2c were evaluated against human lung carcinoma A549, melanoma B16 , colorectal cancer HCT116, human hepatocellular carcinoma HepG2 cancer cell lines, as well as the non-cancerous LO2 cell line using the 3-(4,5-dimethylthiazole-2-yl)-2,5-diphenyltetrazolium bromide (MTT) method. While DPPA exhibited moderate anticancer activity toward A549, B16, HCT116 and HepG2 cells, complexes 2a, 2b, and 2c displayed remarkable efficacy against A549, B16, and HCT116 cells. The cell colonies and wound healing were investigated. Moreover, various aspects of the anticancer mechanisms were explored. The cell cycle analyses revealed that the complexes block cell proliferation of A549 cells during the S phase. Complex 2c induce an early apoptosis, while 2a and 2b cause a late apoptosis. The interaction of 2a, 2b and 2c with endoplasmic reticulum and mitochondria was identified, leading to elevated ROS and Ca 2+ amounts. This resulted in a reduced mitochondrial membrane potential , mitochondrial permeability transition pore opening, and an increase of cytochrome c . Also, ferroptosis was investigated through measurements of intracellular glutathione (GSH), malondialdehyde (MDA), and recombinant glutathione peroxidase (GPX4) protein expression . The pyroptosis was explored via cell morphology, release of lactate dehydrogenase (LDH) and expression of pyroptosis-related proteins. RNA sequencing was applied to examine the signaling pathways . Western blot analyses illuminated that the complexes regulate the expression of Bcl-2 family proteins. Additionally, an in vivo antitumor study demonstrated that complex 2c exhibited a remarkable inhibitory rate of 58.58% in restraining tumor growth. In summary, the findings collectively suggest that the iridium(III) complexes induce cell death via ferroptosis , apoptosis by a ROS-mediated mitochondrial dysfunction pathway and GSDMD-mediated pyroptosis .
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BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
·
2024
·
IF 2.5
Jie Shen,Zhongkai Wu,Yu Zhou,Dashuai Yang,Xin Wang,Bin Yu,Kailiang Zhao,Youming Ding
SLC16A3/monocarboxylate transporter 4 (MCT4) regulates intracellular lactate transport and is highly expressed in many tumors, indicating poor prognosis. It may be related to inducing hypoxia, apoptosis and other mechanisms, but the study of MCT4 in HCC is far from complete. In this study, we first analyzed the expression of SLC16A3 in HCC tumor and non-tumor tissue samples based on TCGA data and immunohistochemistry. Subsequently, the effects of SLC16A3 expression on cell proliferation and invasion were analyzed using hepatocellular carcinoma (HCC) lines, and Western blot (WB) analysis was performed to explore the changes in pathway proteins and ferroptosis proteins. Finally, the drug sensitivity was tested by CCK8 kit. We found that SLC16A3 was significantly upregulated in tumor tissues, and was significantly correlated with TNM stage, histological grade, and macrovascular invasion. TCGA data and WB analysis showed that the high expression of SLC16A3 induced hypoxia, and knockdown could reverse hypoxia and inhibit ERK phosphorylation, thus limiting the malignant behavior of HCC cells. Moreover, knockdown of SLC16A3 significantly increased the level of lipid peroxidation and reactive oxygen species (ROS), while the expressions of GPX4, DHODH and SLC7A11 were inhibited. The expression of SLC16A3 affected the sensitivity of HCC cells to chemotherapy and targeted drugs, and RNA sequencing data suggested that the expression level influenced tumor microenvironment and response to immunotherapy. So, we draw a conclude that SLC16A3 is associated with poor prognosis of HCC. Inhibition of SLC16A3 expression is a potential therapeutic target for HCC.
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Advanced Healthcare Materials
·
2024
·
IF 10
Sijia Wu,Qian Wang,Jun Du,Lejin Zhu,Fujun Yang,Jiacheng Lu,Xueyu Li,Yuhao Li,Jingtao Cui,Yuqing Miao
Sonodynamic therapy (SDT) represents a promising, noninvasive, and precise treatment modality for tumors, demonstrating significant potential in clinical applications. However, the efficiency of sonosensitizers in generating reactive oxygen species (ROS) is often limited by rapid electron-hole recombination. In this study, BiF 3 @BiOI is synthesized via a co-precipitation method, followed by in-situ reduction to decorate it with Pt nanoparticles, resulting in BiF 3 @BiOI@Pt-PVP (BBP) nanocomposite for enhancing SDT efficacy. The formation of the BiF 3 @BiOI heterojunction enhances charge separation ability. The decoration of Pt nanoparticles narrows the bandgap and alters the band positions and Fermi level of BBP, which can effectively mitigate the rapid recombination of electron-hole pairs and facilitate a cascade reaction of ROS, thereby improving ROS generation efficiency with ultrasound excitation. Additionally, bismuth ions in BBP and the generated holes consume glutathione, exacerbating cellular oxidative damage, and triggering PANoptosis and ferroptosis. Furthermore, Pt nanoparticles demonstrate peroxidase-like activity, catalyzing endogenous hydrogen peroxide to oxygen. These functions are helpful against tumors for alleviating hypoxic conditions, reshaping the microenvironment, modulating immune cell infiltration capacity, and enhancing the efficacy of immunotherapy. The dual strategy of forming heterojunctions and sensitization with noble metals effectively enhances the efficacy of sono-catalytic therapy-induced immune activation in tumor treatment.
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OTOLOGY & NEUROTOLOGY
·
2024
·
IF 1.9
Li Yingying,Xu Hui,Shi Jinping,Li Cong,Li Mengxin,Zhang Xiaoling,Xue Qing,Qiu Jingjing,Cui Limei,Sun Yan,Song Xicheng,Chen Liang
Background Gentamicin is a commonly used aminoglycoside antibiotic, with ototoxicity as a significant side effect. Ferroptosis, an iron-dependent form of cell death, has been implicated in a variety of disorders. Whether ferroptosis impacts gentamicin ototoxicity is not yet known. The current work used an in-vitro model to examine the influence of gentamicin-induced ferroptosis on cochlear hair cell damage and probable molecular biological pathways. Methods House Ear Institute-Organ of Corti 1 (HEI-OC1) cells were treated with different concentrations of gentamicin for 24 hours, with or without ferrostatin-1 pretreatment, to observe gentamicin-induced ferroptosis. The role of p53/solute carrier family 7 member 11 (SLC7A11)/glutathione peroxidase 4 (GPX4) signaling in gentamicin-induced ferroptosis was explored by pretreating cells with the p53 inhibitor pifithrin-α (PFT-α). We investigated the effect of gentamicin on cells by assessing cell viability. Cellular proteins were isolated and Western blots were performed to detect changes in the expression of p53, SLC7A11, and GPX4. Fluorescence staining was used to assess levels of reactive oxygen species. An enzymatic detection kit was used to detect glutathione, Fe, and malondialdehyde markers. Results Gentamicin reduced cell viability, glutathione content, and SLC7A11 and GPX4 protein levels, and increased levels of p53 protein, reactive oxygen species, malondialdehyde, and Fe. These effects were largely blocked by pretreatment with ferrostatin-1. Pretreatment with the p53 inhibitor PFT-α prevented the gentamicin-induced reduction in SLC7A11 and GPX4, which alleviated several features of ferroptosis including glutathione depletion, iron overload, and lipid peroxidation build-up. Conclusion Gentamicin induces ferroptosis in the HEI-OC1 cell line, and the mechanism may be related to the p53/SLC7A11/GPX4 signaling pathway.
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Cell Death Discovery
·
2025
·Vol. 11
·期 1
·1-16
·
IF 7
Liang Xue,Tian Ruofei,Li Ting,Wang Hao,Qin Yifei,Qian Meirui,Fan Jing,Wang Dan,Cui Hong-Yong,Jiang Jianli
Pancreatic cancer exhibits high mortality rates with limited therapeutic options. Emerging evidence suggests that the ketogenic diet may act as adjuvant therapy by triggering ferroptosis in cancer cells, though the underlying molecular mechanisms remain unclear. This study aims to investigate the molecular mechanisms linking ketogenic metabolism and ferroptosis, with an emphasis on key regulatory proteins. We demonstrated that pancreatic adenocarcinoma (PAAD) tissues significantly enhanced ketogenic and ferroptosis phenotypes compared to normal tissues, both correlating with poorer patient prognosis. These phenotypes showed strong interdependence mediated by CAV1. In the pancreatic tumor microenvironment, CAV1 was predominantly expressed in tumor cells. Through in vitro cell experiments, we clarified that Na-OHB downregulated CAV1 expression in pancreatic cancer cells, inhibiting the transcription of the CAV1/AMPK/NRF2 downstream ferroptosis-protective genes SLC7A11 and SLC40A1. Additionally, we demonstrated the interaction between CAV1 and SLC7A11 molecules; when CAV1 was downregulated, it affected the stability of SLC7A11, leading to the ubiquitination and degradation of the translated SLC7A11 protein. Through these dual mechanisms, Na-OHB caused Fe 2+ overload, lipid peroxidation accumulation, and oxidative stress in pancreatic cancer cells, ultimately triggering ferroptosis. In ketogenic diet-fed tumor-bearing mouse models, we also observed a significant increase in lipid peroxidation and other related biomarkers, while CAV1 and SLC7A11 levels were markedly decreased compared to the normal diet group. Our findings identify CAV1 as a pivotal molecular link between ketogenic metabolism and ferroptosis in pancreatic cancer. The multi-level regulatory axis involving CAV1-mediated transcriptional regulation and post-translational modifications provides mechanistic insights into ketogenic diet-induced ferroptosis, suggesting potential therapeutic targets for pancreatic cancer adjuvant treatment.
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ACS Nano
·
2025
·
IF 16
Mengsi Zhang,Hao Zheng,Xuanqi Zhu,Shuwei Liu,Hao Jin,Yang Chen,Lanlan Wan,Songling Zhang,Hao Zhang
Disulfidptosis and ferroptosis are recently identified programmed cell deaths for tumor therapy, both of which highly depend on the intracellular cystine/cysteine transformation on the cystine transporter solute carrier family 7 member 11/glutathione/glutathione peroxidase 4 (SLC7A11/GSH/GPX4) antioxidant axis. However, disulfidptosis and ferroptosis are usually asynchronous due to the opposite effect of cystine transport on them. Herein, systematic glucose deprivation, by both inhibiting upstream glucose uptake and promoting downstream glucose consumption, is proposed to synchronously evoke disulfidptosis and ferroptosis. As an example, Au nanodots and Fe-apigenin (Ap) complexes coloaded FeOOH nanoshuttles (FeOOH@Fe-Ap@Au NSs) are employed to regulate the SLC7A11/GSH/GPX4 axis for performing disulfidptosis- and ferroptosis-mediated tumor therapy synchronously. In this scenario, Au nanodots exhibit glucose oxidase-like activity when consuming massive glucose. Meanwhile, Ap can inhibit glucose uptake by downregulating glucose transporter 1, depriving glucose fundamentally. The systematical glucose deprivation limits the supplement of NADPH and suppresses cystine/cysteine transformation on the SLC7A11/GSH/GPX4 axis, thus solving the contradiction of cystine transport on disulfidptosis and ferroptosis. In addition, the efficient delivery of exogenous iron ions by FeOOH@Fe-Ap@Au NSs and self-supplied H2O2 through Au nanodots-catalytic glucose oxidation facilitate intracellular Fenton reaction and therewith help to amplify ferroptosis. As a result of synchronous occurrence of disulfidptosis and ferroptosis, FeOOH@Fe-Ap@Au NSs exhibit good efficacy in an ovarian cancer therapeutic model.
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Reproductive Sciences
·
2025
·
IF 2.5
Ma Qianwen,Wu Lifei,Wu Jianfei,Ni Binfei,Wang Jiajia,Song Shiyan
Objective To investigate the mechanism in the progression of decreased ovarian reserve (DOR). Methods Three-month-old female SD rats were employed and randomly divided into the model group and the normal group. The model group was intraperitoneally injected with 4-vinylcyclohexene diepoxide (VCD). Thereafter, blood sample from the abdominal aorta was taken, and rats were sacrificed, and ovarian tissues were obtained by laparotomy. Results HE staining results revealed that the model group exhibited significantly reduced ovarian volume, increased follicular atresia, and decreased quantities of growing follicles and corpus luteum, thereby indicating degraded reserve function of ovarian. TEM images revealed that prominent autophagic vacuoles could be observed in the model group, accompanied by the mitochondria shrinkage and generation of the autophagosome. The expression of Pink1, Parkin, BNIP3L and LC3II genes in ovaries of the model group was significantly higher than those of the normal group ( P < 0.05). In addition, the protein expression of Pink1, Parkin, BNIP3L and LC3II in ovaries of the model group were higher than those of the normal group ( P < 0.05). The expression of Fe 2+ and GSH in oocytes of the model group was higher than those of the normal group ( P < 0.05). The expression of FTH1 and GPX4 in oocytes of the model group was significantly higher than those of the normal group ( P < 0.05). Conclusions Mitochondrial autophagy and ferroptosis may participate in the progression of decreased ovarian reserve (DOR).
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AMERICAN JOURNAL OF PATHOLOGY
·
2025
·
IF 3.6
Lin Xu,Yuanyuan Zhao,Yang Yang,Enbo Qi,Boao Liu,Peili Zhuang,Shiyi Song,Tingmin Chang,Zhiguo Chen,Xiaohong Kang,Xiwen Xiong
Alcohol-related liver disease (ALD), a consequence of excessive alcohol use, manifests across a broad spectrum of liver damage, ranging from steatosis to cirrhosis. DEPDC5 is a component of the GATOR1 complex, which functions as a repressor of the amino acid-sensing branch of the mTORC1 pathway. In this study, hepatocyte specific Depdc5 knockout mice (Depdc5 △Hep ) were generated and it was found that aberrant activation of mTORC1 caused by Depdc5 deletion led to exacerbated ER stress and hepatocyte ferroptosis in the livers of ethanol-fed mice. Torin-1, an ATP-competitive mTOR inhibitor, suppressed the mTORC1 activity and reversed the effects of Depdc5 deletion on ER stress and ferroptosis in ethanol-fed mouse livers. Furthermore, pharmacological relief of ER stress using TUDCA or inhibition of ferroptosis with liproxstatin-1 both alleviated the liver abnormalities induced by Depdc5 ablation in ethanol-fed mice. Additionally, the research uncovered that ER stress functions as an upstream signal of ferroptosis in the progression of ALD. These findings provide novel in vivo evidence that sustained mTORC1 activation leads to alcoholic liver injury by inducing ER stress and ferroptosis, suggesting that targeting these pathways may represent a potential therapeutic strategy for ALD.
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TOXICOLOGY AND APPLIED PHARMACOLOGY
·
2025
·
IF 3.4
Lishan Lin,Danhui Huang,Haohua Huang,Lingyan Xie,Yi Huang,Cuiping Ye,Lanhe Chu,Yujie Qiao,Xiaojing Meng,Shaoxi Cai,Hangming Dong
Inhaled environmental allergens, such as house dust mites (HDM), have been shown to induce an inflammatory reaction, tissue injury, and increased airway sensitivity in the lungs, ultimately leading to the development of allergic asthma. The imbalance of respiratory microbiota and metabolites plays a crucial role in the progression of allergic asthma. However, there is limited knowledge available regarding the alterations in respiratory microbiota and metabolites and their impact on the host in the context of asthma. The aim of this study was to investigate the potential pathways involved in the development of asthma through the analysis of lung flora and metabolites. A mouse model of house dust mite (HDM)-induced asthma was established, and alveolar lavage samples were collected for microbiome 16S rRNA sequencing and untargeted metabolic analysis. Microbiological analyses indicated a significant alteration in the microbiota after 4 and 6 weeks of HDM nebulisation stimulation. This was characterized by a decrease in microbial diversity, as well as reductions in the relative proportion of Gallionella and Lactobacillus . Conversely, the abundance of Flavobacterium and Ralstonia increased in the HDM4W and HDM6W groups, respectively. Metabolomic analyses revealed seven distinct metabolites, among them L-malic acid, which were linked to signaling pathways in a mouse model of HDM-induced asthma. The correlation analysis demonstrated a positive association between L-malic acid and Rhodanobacter and Nocardioides . L-malic acid was discovered to be efficacious in reducing airway inflammation in mice with house dust mite-induced asthma. Further analysis revealed that this change was linked to lipid peroxidation and changes in ferroptosis markers, namely GPX4 and FTH. These findings suggest that L-malate inhibits ferroptosis. However, the introduction of ferroptosis inducers, such as Erastin, was observed to negate the beneficial effect of butyrate. In summary, this research implies that the respiratory microbiota metabolite L-malic acid lessens airway inflammation in asthma by inhibiting ferroptosis, offering a potential approach for managing asthma.
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Biomaterials Research
·
2025
·
IF 9.6
Yangjing Su,Yunong Zeng,Minjie Zhou,Meihui Liao,Ping Qin,Rong Wu,Jiaochan Han,Xiaoqi Liang,Ze Wang,Jingjing Jiang,Zhichao Yu,Xintao Huang,Kaixin Ding,Peiheng Guo,Yi He,Ying Du,Tingting Duan,Haitao Yuan,Yuewei Ge,Ali Chen,Wei Xiao
Acetaminophen (APAP) overdose has long been recognized as the main cause of drug-induced liver injury (DILI), characterized by glutathione (GSH) depletion and reactive oxygen species (ROS) accumulation, leading to ferroptosis and inflammatory responses. There is an urgent need for liver-protective agents to combat ferroptosis, modulate oxidative stress, and ameliorate inflammation. Catechin, a well-known polyphenol compound, has been shown to have antioxidant potential. However, its protective role on APAP-induced liver injury (AILI) has not been elucidated. In this study, we evaluated the modulating effects of catechin on AILI and observed that catechin attenuated liver injury by reducing inflammation. Mechanistically, catechin alleviated hepatic oxidative stress by inhibiting ROS accumulation, malondialdehyde (MDA) production, and GSH depletion. Furthermore, catechin, as a hepatic injury reparative agent, could counteract APAP-induced hepatocyte ferroptosis by activating the xCT/GPX4 pathway, and is expected to be a novel natural inhibitor of ferroptosis. Additionally, the transcriptomic results indicated that the inhibition of Stat1 by catechin is important for the management of AILI. Inhibition of signal transducer and activator of transcription 1 (STAT1) expression, achieved through the use of the STAT1 inhibitor fludarabine in vivo and small interfering RNA (siRNA) in vitro, was confirmed to attenuate APAP-induced ferroptosis. In conclusion, the present study identified a novel natural drug inhibitor of ferroptosis and revealed its mechanism of action to inhibit ferroptosis, regulate oxidative stress, and ameliorate inflammation in AILI. This further provides new insights into the novel natural ferroptosis inhibitors for the treatment of ROS-related inflammatory diseases.
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Small
·
2022
·Vol. 18
·期 12
·2106568
·
IF 15.153
Anwei Zhou,Tianliang Fang,Kerong Chen,Yurui Xu,Zhuo Chen,Xinghai Ning
Ferroptosis is a type of nonapoptotic cell death and is gradually emerging as an important anticancer treatment. However, its therapeutic efficacy is impaired by low intracellular levels of reactive oxygen species (ROS) and long-chain polyunsaturated fatty acids, significantly limiting its therapeutic potential. Herein, a multimodal strategy to improve ferroptosis is presented, in which a state-of-art engineered erythrocyte, termed as sonodynamic amplified ferroptosis erythrocyte (SAFE), is developed for simultaneously activating ferroptosis and oxygen-riched sonodynamic therapy (SDT). SAFE is composed of internalizing RGD peptide and red blood cell membrane hybrid camouflaged nanocomplex of hemoglobin, perfluorocarbon, ferroptosis activator (dihomo-γ-linolenic acid, DGLA), and sonosensitizer verteporfin. It is identified that SAFE, under ultrasound stimulation, can not only substantially supply oxygen to overcome tumor hypoxia associated therapeutic resistance, but effectively activate ferroptosis through the coeffect of SDT triggered ROS production and DGLA mediated lipid peroxidation. In vivo studies reveal that SAFE selectively accumulates in tumor tissues and induces desirable anticancer effects under mild ultrasound stimulation. Importantly, SAFE can effectively inhibit tumor growth with minimal invasiveness, resulting in a prolonged survival period of mice. Therefore, a multimodal ferroptosis therapy driven by oxygen-riched sonodynamic peroxidation of lipids, significantly advancing synergistic cancer treatment, is presented.
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