Materials Today Bio
·
2025
·
IF 10.2
Mingyue Yan,Kehao Hou,Jinpeng Zhao,Shuangshan Li,Xiaolin Wu,Shichao Bi,Jing Yu,Tianrui Wang,Yingze Zhang
The characteristic pathological manifestations of rheumatoid arthritis (RA) include inflammatory cell infiltration, abnormal synoviocyte proliferation, and progressive bone and cartilage destruction. An excessive buildup of reactive oxygen species (ROS) within the joints is a critical factor promoting RA pathological progression. In this study, we innovatively employed a hard template-restricted controlled sintering carbonization strategy to fabricate ultra-small Fe 3 O 4 @C nanoparticles with hierarchical structures. The ultra-small Fe 3 O 4 @C nanoparticles exhibit multiple natural enzyme-mimic catalytic activity, effectively diminishing intracellular ROS levels in macrophages, while also facilitating the polarization toward the M2 phenotype, and significantly suppresses the production of pro-inflammatory cytokines. Mechanistic investigations reveal that Fe 3 O 4 @C significantly suppresses ferroptosis in synoviocytes and chondrocytes through regulation of the SLC7A11/GPX4 signalling pathway, thereby alleviating synovial tissue erosion and promoting type II collagen synthesis. In the collagen-induced arthritis mouse model, Fe 3 O 4 @C exhibited remarkable anti-inflammatory and chondroprotective effects, providing an innovative nanozyme therapeutic approach for RA treatment.
研究领域:
纳米医学
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风湿病学
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免疫学
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生物医学工程
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氧化还原生物学
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DOI
PubMed
高影响因子
Nutrients
·
2023
·Vol. 15
·期 5
·1090
·
IF 5.9
Yunpeng Zhang,Shuang Liu,Jing Peng,Shifeng Cheng,Qingling Zhang,Nan Zhang,Zandong Zhou,Yue Zhang,Yang Zhao,Tong Liu
Mitochondria-dependent ferroptosis plays an important role in the pathogenesis of doxorubicin (DOX)-induced cardiotoxicity (DIC), which remains a clinical challenge due to the lack of effective interventions. Cerium oxide (CeO2), a representative nanozyme, has attracted much attention because of its antioxidant properties. This study evaluated CeO2-based nanozymes for the prevention and treatment of DIC in vitro and in vivo by adding nanoparticles (NPs), which were synthesized by biomineralization, to the culture or giving them to the mice, and the ferroptosis-specific inhibitor ferrostatin-1 (Fer-1) was used as control. The prepared NPs exhibited an excellent antioxidant response and glutathione peroxidase 4 (GPX4)-depended bioregulation, with the additional merits of bio-clearance and long retention in the heart. The experiments showed that NP treatment could significantly reverse myocardial structural and electrical remodeling, and reduce myocardial necrosis. These cardioprotective therapeutic effects were associated with their ability to alleviate oxidative stress, mitochondrial lipid peroxidation, and mitochondrial membrane potential damage, with a superior efficiency to the Fer-1. The study also found that the NPs significantly restored the expression of GPX4 and mitochondrial-associated proteins, thereby restoring mitochondria-dependent ferroptosis. Therefore, the study provides some insights into the role of ferroptosis in DIC. It also shows that CeO2-based nanozymes could be a promising prevention and treatment candidate as a novel cardiomyocyte ferroptosis protector to mitigate DIC and improve prognosis and quality of life in cancer patients.Keywords:doxorubicin-induced cardiomyopathy;ferroptosis;mitochondria;nanozyme;oxidative stress;biomineralization
研究领域:
心脏病学
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纳米技术
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药理学
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分子生物学
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DOI
PubMed
高影响因子
Cell Communication and Signaling
·
2024
·Vol. 22
·期 1
·1-20
·
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.
研究领域:
心脏病学
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细胞生物学
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病理生理学
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DOI
PubMed
高影响因子
EUROPEAN JOURNAL OF PHARMACOLOGY
·
2024
·
IF 4.2
Yongmei Li,Fengxin Zheng,Shiqi Zhong,Kunlu Zhao,Hui Liao,Jiacheng Liang,Qiang Zheng,Huicong Wu,Shifan Zhang,Ying Cao,Ting Wu,Jianxin Pang
Hyperuricemic nephropathy (HN) is characterized by renal fibrosis and tubular necrosis caused by elevated uric acid levels. Ferroptosis, an iron-dependent type of cell death, has been implicated in the pathogenesis of kidney diseases. The objective of this study was to explore the role of ferroptosis in HN and the impact of a ferroptosis inhibitor, ferrostatin-1 (Fer-1). The study combined adenine and potassium oxonate administration to establish a HN model in mice and treated HK-2 cells with uric acid to simulate HN conditions. The effects of Fer-1 on the renal function, fibrosis, and ferroptosis-associated molecules were investigated in HN mice and HK-2 cells treated with uric acid. The HN mice presented with renal dysfunction characterized by elevated tissue iron levels and diminished antioxidant capacity. There was a significant decrease in the mRNA and protein expression levels of SLC7A11, GPX4, FTL-1 and FTH-1 in HN mice. Conversely, treatment with Fer-1 reduced serum uric acid, serum creatinine, and blood urea nitrogen, while increasing uric acid levels in urine. Fer-1 administration also ameliorated renal tubule dilatation and reduced renal collagen deposition. Additionally, Fer-1 also upregulated the expression levels of SLC7A11, GPX4, FTL-1, and FTH-1, decreased malondialdehyde and iron levels, and enhanced glutathione in vivo and in vitro . Furthermore, we first found that Fer-1 exhibited a dose-dependent inhibition of URAT1, with the IC 50 value of 7.37 ± 0.66 μM. Collectively, the current study demonstrated that Fer-1 effectively mitigated HN by suppressing ferroptosis, highlighting the potential of targeting ferroptosis as a therapeutic strategy for HN.
研究领域:
肾病学
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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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DOI
PubMed
高影响因子
JOURNAL OF HAZARDOUS MATERIALS
·
2024
·
IF 12.2
Lin Zhang,Wen-Yao Shi,Jia-Ying Xu,Yan Liu,Shi-Jia Wang,Jia-Yang Zheng,Yun-Hong Li,Lin-Xi Yuan,Li-Qiang Qin
Although selenium (Se) and cadmium (Cd) often coexist naturally in the soil of China, the health risks to local residents consuming Se-Cd co-enriched foods are unknown. In the present study, we investigated the effects of chemical-based selenocystine (SeCys 2 ) on cadmium chloride-induced human hepatocarcinoma (HepG2) cell injury and plant ( Cardamine hupingshanensis )-derived SeCys 2 against Cd-induced liver injury in mice. We found that chemical- and plant-based SeCys 2 showed protective effects against Cd-induced HepG2 cell injury and liver damage in mice, respectively. Compared with Cd intervention group, co-treatment with chemical- or plant-based SeCys 2 both alleviated liver toxicity and ferroptosis by decreasing ferrous iron, acyl-CoA synthetase long-chain (ACSL) family member 4, lysophosphatidylcholine acyltransferase 3, reactive oxygen species and lipid peroxide levels, and increasing ACSL3, peroxisome proliferator-activated receptor α, solute carrier family 7 member 11 (SLC7A11) and glutathione and glutathione peroxidase 4 (GPX4) levels. In conclusion, chemical- and plant-based SeCys 2 alleviated Cd-induced hepatotoxicity and ferroptosis by regulating SLC7A11/GPX4 signaling and lipid peroxidation. Our findings indicate that potential Cd toxicity from consuming foods grown in Se- and Cd-rich soils should be re-evaluated. This study offers a new perspective for the development of SeCys 2 -enriched agricultural products.
研究领域:
毒理学
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药理学
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细胞生物学
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植物科学
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DOI
PubMed
高影响因子
Redox Biology
·
2024
·
IF 10.7
Xin Zhong,Kangwei Wang,Yonghua Wang,Luya Wang,Sudan Wang,Weijian Huang,Zhuyin Jia,Shan-Shan Dai,Zhouqing Huang
Continuous remodeling of the heart can result in adverse events such as reduced myocardial function and heart failure. Available evidence indicates that ferroptosis is a key process in the emergence of cardiac disease. P2 family purinergic receptor P2X7 receptor (P2X7R) activation plays a crucial role in numerous aspects of cardiovascular disease. The aim of this study was to elucidate any potential interactions between P2X7R and ferroptosis in cardiac remodeling stimulated by angiotensin II (Ang II), and P2X7R knockout mice were utilized to explore the role of P2X7R and elucidate its underlying mechanism through molecular biological methods. Ferroptosis is involved in cardiac remodeling, and P2X7R deficiency significantly alleviates cardiac dysfunction, remodeling, and ferroptosis induced by Ang II. Mechanistically, Ang II interacts with P2X7R directly, and LYS-66 and MET-212 in the C-type domain form a binding complex with Ang II. P2X7R blockade influences HuR-targeted GPX4 and HO-1 mRNA stability by affecting the shuttling of HuR from the nucleus to the cytoplasm and its expression. These results suggest that focusing on P2X7R could be a possible therapeutic approach for the management of hypertensive heart failure.
研究领域:
心血管疾病
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分子生物学
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药理学
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DOI
PubMed
高影响因子
Cell Death & Disease
·
2026
·
IF 12.2
Liu Yanyan,Guan Chenxi,Xu Linlin,Yang Jianhua,Wang Jinglei,Yang Si,Chen Jiaxiang
Impaired Leydig cell function leads to low testosterone levels, which is associated with male reproductive developmental defects and functional disorders. Exposure to di(2-ethylhexyl) phthalate (DEHP), an endocrine-disrupting chemical, can cause damage to Leydig cells, yet the underlying mechanism remains unclear. In this study, we found that DEHP exposure decreased serum testosterone levels and triggered ferroptosis of mouse Leydig cells by inhibiting GPX4 expression. Subsequently, mono(2-ethylhexyl) phthalate (MEHP), the primary active metabolite of DEHP, was shown to suppress the transcription of Gpx4 gene in TM3 cells by downregulation of HOXA3, which bound to the −264 to −258 region (RE3) of Gpx4 gene promoter. Concurrently, MEHP promoted HSC70 to recognize and degradate GPX4 protein via chaperone-mediated autophagy (CMA). Furthermore, both overexpression of HOXA3 and inhibition of CMA significantly abrogated MEHP-induced ferroptosis of TM3 cells through upregulating the expression of GPX4. Ultimately, tannic acid (TA), a natural polyphenol, was identified to increase the expression of GPX4 and inhibit MEHP-induced ferroptosis of TM3 cells, thereby alleviating DEHP-caused testicular damage in mice through the upregulation of HOXA3 and inhibition of CMA.
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高影响因子
ENVIRONMENT INTERNATIONAL
·
2026
·
IF 10.2
Fan Yu,Shihao Luo,Zhengrong Zhou,Feixia Chen,Jiawei Ying,Qiufang Wu,Yize Wu,Shihua Chen,Xinxin Yao,Feiqin Xie,Wenhui Xu,Ke Xu,Renyi Peng
Cypermethrin (CY), a pyrethroid insecticide, accumulated in aquatic environments and exertd toxic effects on aquatic organisms, impairing their development, nervous system, and immune function. Polystyrene nanoparticles (PS-NPs) readily adsorbed organic contaminants like CY, forming complex pollution systems that resulted in synergistic toxicities. However, the mechanisms behind their hepatotoxicity remained unclear. In this study, both in vivo and in vitro experiments demonstrated that co-exposure to PS-NPs and CY significantly induced liver injury and steatosis in zebrafish larvae, while activating the key lipid synthesis regulator sterol regulatory element-binding protein 1 (SREBP1) in Hep G2 cells. This process displayed typical features of ferroptosis, including oxidative stress, mitochondrial damage, iron dysregulation, and suppression of the antioxidant enzyme glutathione peroxidase 4 (GPX4). Correlation analysis showed a close association between ferroptosis and steatosis. Physiological and genetic verification revealed that Erastin aggravated lipid accumulation by inhibiting GPX4 expression, activating the SREBP1/SCD1 lipid synthesis pathway. Conversely, Ferrostatin-1 (Fer-1), a ferroptosis inhibitor, alleviated oxidative stress, iron overload, and lipid accumulation, while GPX4 overexpression reversed SREBP1/SCD1 activation and improved lipid accumulation, peroxidation, and ferroptosis. This study revealed a novel mechanism by which PS-NPs and CY co-exposure induced ferroptosis-mediated hepatic steatosis through GPX4. These findings provided new insights into the hepatometabolic toxicity of complex pollutants and identified potential targets for preventing related liver diseases.
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PubMed
高影响因子
Frontiers in Bioscience-Landmark
·
2025
·Vol. 30
·期 6
·36615
·
IF 3.1
Shanli Wu,Gun Yang,Xiaosha Wen,Yi Lin,Shenglong Wang,Jing Wang,Quan Liu,Dixian Luo
Background:Aldo-keto reductase 1B10 (AKR1B10) is expressed in various malignant tissues. Several studies have highlighted the essential function of AKR1B10 in lipid metabolism and in the detoxification of lipid peroxides. The aim of this research was to explore the role of AKR1B10 in the susceptibility of MDA-MB-231 cells to ferroptosis. These cells serve as a model for triple-negative breast cancer (TNBC).Methods:Lentiviral transfection was used to establish stable cell lines with high or low expression of AKR1B10. Our model of ferroptosis used the ferroptosis activator RSL3, and the specific ferroptosis inhibitor ferrostatin-1 (Fer-1) to rescue cell death. Stable cell lines were treated with the specific inhibitor OSU-T315 directed against phosphorylation of Ser473 in protein kinase B (AKT) and Ser9 in glycogen synthase kinase 3 beta (GSK3β), either alone or in combination with RSL3. A fatty acid stress model was established using palmitic acid (PA) or arachidonic acid (AA), either in the presence or absence of serum starvation and with or without co-treatment with RSL3. Cell viability was evaluated with the cell counting kit-8 (CCK8) assay and lipid peroxidation levels by flow cytometry after staining with C11 BODIPY 581/591. Exploration of the underlying mechanisms was conducted through RNA sequencing and bioinformatics analysis. Western blotting was performed to evaluate protein levels, and quantitative real-time polymerase chain reaction (qPCR) was used to evaluate transcript levels.Results:Western blot and qPCR analyses validated the successful establishment of stable MDA-MB-231 cell lines with and without AKR1B10 overexpression. Cell viability and lipid reactive oxygen species (ROS) assays showed that AKR1B10 suppressed ferroptosis in the RSL3-induced cell death model. Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Set Enrichment Analysis (GSEA) analyses indicated the phosphatidylinositol 3-kinase (PI3K)-AKT pathway was likely to play a role in the underlying mechanisms. AKR1B10 increased the expression of glutathione peroxidase 4 (GPX4), thus potentially implicating the AKT/GSK3β/nuclear factor erythroid 2-related factor 2 (NRF2)/GPX4 pathway in the mechanism. These changes in protein levels were also observed by Western blot analysis after 6 h of RSL3 treatment. Under the influence of RSL3, the transcript levels of NRF2-related genes including GPX4, ferritin heavy chain 1 (FTH1), heme oxygenase 1 (HO-1), and NAD(P)H quinone dehydrogenase 1 (NQO-1) were significantly elevated in the AKR1B10 overexpression cell line, whereas that of prostaglandin-endoperoxide synthase 2 (PTGS2) was significantly reduced. Similar changes were observed after treatment with OSU-T315. AKR1B10 was found to suppress the sensitivity to ferroptosis induced by treatment with OSU-T315, PA, or AA. These phenomena were rescued by the ferroptosis inhibitor Fer-1.Conclusions:AKR1B10 appears to be an important mechanism protecting MDA-MB-231 cells from ferroptosis, possibly through the AKT Ser473/GSK3β Ser9/NRF2/GPX4 pathway. AKR1B10 may be a key factor underlying the therapeutic effect of RSL3 under different exogenous fatty acid microenvironments.
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PubMed
高影响因子
Theranostics
·
2025
·Vol. 15
·期 17
·8757
·
IF 13.3
Hui Yuan,Xiongwu Li,Muhua Yu,Youde Cao,Lingcheng Wu,Suyujie Shi,Yaying Yang,Kexiao Yu,Bing Liang
Background: Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer, characterized by the absence of targeted therapies and poor clinical outcomes. The development of novel, effective therapeutic strategies is urgently required to improve patient prognosis. Ferroptosis, a regulated form of cell death, has recently emerged as a promising therapeutic approach for TNBC. Objectives: This study aims to evaluate the efficacy of an injectable silk fibroin (SF)-based platform in treating TNBC and to explore the underlying mechanisms involved. Methods: We engineered an injectable SF platform consisting of magnetic, thermoresponsive silk fibroin-based hydrogels (IMSFs) coupled with temporally controlled TAT-Beclin1 delivery. Ferroptosis induction was quantified using the C11-BODIPY probe and transmission electron microscopy (TEM). To investigate the molecular mechanisms, RNA sequencing, Western blotting, and co-immunoprecipitation were performed. Additionally, enzyme-linked immunosorbent assay (ELISA) and flow cytometry were used to assess immune responses. Results: In the presence of an alternating magnetic field (AMF), IMSFs induce localized hyperthermia (42-45 °C) and catalyze Fenton reaction-driven reactive oxygen species (ROS) generation through Fe²⁺/Fe³⁺ release. The resulting ROS synergize with sorafenib release to inhibit the Xc⁻ system via the AMPK-Beclin1-SLC7A11 axis, leading to the local suppression of glutathione peroxidase 4 (GPX4) activity and the initiation of a ferroptosis cascade. Temporal delivery of TAT-Beclin1 prevents premature activation of autophagy, which could otherwise dampen ferroptosis. Instead, this approach leverages autophagy-ferroptosis synergy to amplify immunogenic cell death (ICD). This, in turn, activates CD8 + T cells, triggering interferon-gamma (IFN-γ)-mediated downregulation of SLC7A11 and establishing a self-amplifying cascade of “ferroptosis-autophagy-immunity” loop that induces oxidative stress and leads to enhanced anti-tumor effects. Conclusion: The injectable SF platform, incorporating sequential therapeutic modules, demonstrates potent anti-tumor efficacy and holds significant promise for clinical translation in the treatment of TNBC.
研究领域:
肿瘤学
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纳米医学
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细胞死亡机制
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免疫治疗
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生物材料
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靶向治疗
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DOI
PubMed
高影响因子
PHYTOMEDICINE
·
2026
·
IF 8.3
XiaoYang Qu,LiJuan Chen,JiangHua He,YuFei Fang,Jing Sun,ZhiYing Yu,Zhen Yang,ZiJing Zhang,JianBo Chen,Ling Dong
Background Epilepsy is a prevalent neurological disorder characterized by recurrent seizures and has limited effectiveness of available clinical treatments. Ferroptosis of neurons is one of the main mechanisms of epilepsy. Arisaema Cum Bile (ACB) is a traditional Chinese medicine that is prepared by fermenting animals bile with Rhizoma Arisaematis rhizomes, has demonstrated therapeutic effects on epilepsy and other nervous system diseases. Furthermore, the active components responsible for the anti-epileptic effects of ACB and the intrinsic mechanisms are still unclear. Purpose This study aims to clarify the principal bioactive constituents of ACB and their mechanisms in the treatment of epilepsy. It also seeks to provide data support for its clinical application in antiepileptic combination therapy. Method Pentylenetetrazol injections were used to induce epilepsy in rats. ACB and brain metabolites were identified via UPLC-Q-Exactive Orbitrap MS/MS, and active components were predicted through bioinformatics analysis. In vivo , ACB and hyodeoxycholic acid (HDCA) were administered by gavage, and the effects on oxidative stress, inflammation, and cognitive impairment were evaluated. Additionally, ferroptosis-related protein and gene expression were analyzed using western blot, PCR, immunofluorescence, and flow cytometry. In vitro , using primary neurons and HT22 cells, with electrophysiology employed to assess neuronal activity and glutamate used to induce ferroptosis in HT22 cells, in order to explore how HDCA alleviates epilepsy by inhibiting neuronal ferroptosis. Result A total of 37 chemical components were identified from the ACB, of which 10 active constituents can cross the blood-brain barrier, including steroids and terpenoids. Bioinformatics analysis suggests that HDCA may be one of the key active components responsible for ACB anti-epileptic effects and ferroptosis may represent a crucial underlying therapeutic mechanism. Studies in animals have demonstrated that treatment with ACB and HDCA reduced the frequency and severity of seizures in epileptic rats, mitigated hippocampal neuronal damage, improved post-epileptic cognitive learning capacity, alleviated neuroinflammatory injury and decreased markers of ferroptosis. This neuroprotective effect likely occurs through activation of the p53/Nrf2/GPX4 signaling pathway. Further in vitro cell experiments demonstrated that HDCA can inhibit the generation of action potentials in primary hippocampal neurons, protects HT22 neurons from glutamate-induced cell death, an effect that is reduced by Nrf2 inhibitors. These findings corroborate earlier bioinformatics analyses, confirming that the neuroprotective effects of HDCA are closely linked to Nrf2-mediated ferroptosis pathways. Conclusion HDCA is a key component of ACB anti-epileptic effects, potentially inhibiting ferroptosis through the p53/Nrf2/GPX4 pathway to reduce epilepsy.
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PubMed
高影响因子
JOURNAL OF MEDICINAL CHEMISTRY
·
2022
·
IF 8.039
Haohao Wang,Di Wu,Chunyu Gao,Hongbo Teng,Yan Zhao,Zhongmei He,Weijia Chen,Ying Zong,Rui Du
In this study, 70 new seco-lupane triterpene derivatives were designed, synthesized, and characterized, and their in vitro anticancer activities were evaluated. Structure–activity relationship studies showed that most compounds inhibited the growth of a variety of tumor cells in vitro. With the extension of alkyl chains, the activity of azole compounds gradually increased while that of indole compounds first increased and then decreased. Moreover, all indole derivatives showed stronger anticancer activity than azole derivatives. In addition, compound 21 showed the strongest inhibitory effect on HepG2 cells with an IC50 value of 0.97 μM. Mechanistic studies showed that compound 21 coregulates the cell death process by inducing ferroptosis and regulating the cell cycle. In conclusion, compound 21 can be used as a ferroptosis inducer and cycle blocker to regulate the HepG2 death process, and it has the potential to become an effective new drug for the treatment of hepatocellular carcinoma.
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高影响因子
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