Advanced Healthcare Materials
·
2022
·Vol. 12
·期 3
·2202009
·
IF 11.092
Yi Zhang,Liyi Peng,Ke Hu,Ning Gu
Ferroptosis has recently become a research hotspot, and the induction of tumor cell ferroptosis has emerged as a powerful method for tumor therapy. However, the efficiency of tumor cell ferroptosis induction remains unmet for clinical use, which may be attributed to the large discrepancies between in vitro and in vivo models. To address this issue, in this study, a hydrogel platform with stress relaxation is utilized to develop a multicellular spheroid model of the DLD1 colon cancer cell line through cancer cell self-organization. The spheroids are highly similar to real tumor tissue, and ferroptosis resistance at the transcriptional, protein, and cellular levels. Collaboration of the ferroptosis induction reagent erastin and the nanoenzyme MnZnFe 2 O 4 @PEG-COOH to overcome the ferroptosis resistance of the spheroids is also demonstrated. Taken together, this study demonstrates the effectiveness of the model developed using this hydrogel platform for further mechanistic studies, and for the assessment of novel cancer treatment strategies based on ferroptosis.
✓ 已验证
DOI
PubMed
高影响因子
Biomed Research International
·
2022
·
IF 3.246
Hongwei Shi,Yue Yan,Hong Yang,Peng Pu,Heng Tang
Objective. Pirarubicin (THP) is one of anthracycline anticancer drugs. It is widely used in the treatment of various cancers, but its hepatotoxicity cannot be ignored. Schisandrin B (SchB) is a traditional liver-protecting drug, which has the ability to promote mitochondrial function and upregulate cellular antioxidant defense mechanism. However, whether it can resist THP-induced hepatotoxicity has not been reported. The purpose of this study was to observe and explore the effect of SchB on THP-induced hepatotoxicity and its potential mechanism by adding SchB to the diet of rats with THP-induced hepatotoxicity. Methods. The rat model of THP-induced hepatotoxicity was established and partly treated with SchB diet. The changes of serum liver function indexes ALT and AST were observed. The histomorphological changes of liver were observed by HE staining. The biomarker levels of oxidative stress in rat serum and liver were measured to observe oxidative stress state. The expressions of ferroptosis-related protein GPX4 and oxidative stress-related protein were detected by Western blot. Primary hepatocytes were prepared and cocultured with THP, SchB, and Fer-1 to detect the production of reactive oxygen species (ROS) and verify the above signal pathways. Results. THP rats showed a series of THP-induced hepatotoxicity changes, such as liver function damage, oxidative stress, and ferroptosis. SchB diet effectively alleviated these adverse reactions. Further studies showed that SchB had strong antioxidant and antiferroptosis abilities in THP-induced hepatotoxicity. Conclusion. SchB has obvious protective effect on THP-induced hepatotoxicity. The mechanism may be closely related to inhibiting oxidative stress and ferroptosis in the liver.
✓ 已验证
DOI
PubMed
高影响因子
Biomolecules
·
2026
·Vol. 16
·期 10
·1507
·
IF 5.6
Ting Ge,Yifan Wen,Jiale Zhao,Wenjia Wang,Wenwen Xu,Bo Li,Yibing Wang,Weihua Zhang,Enping Zhang
Litter size is a critical trait determining the economic efficiency of sheep production. Ferritin heavy chain 1 (FTH1), a key iron-storage protein, plays an important role in regulating cellular susceptibility to ferroptosis. Based on our previous observation that ferroptosis-related pathways differ between ovaries from single-lamb and multi-lamb Hu ewes, this study investigated the role ofFTH1in regulating ferroptosis and granulosa cell (GC) function in sheep.FTH1expression was examined in ovarian tissues and GCs from Hu sheep with different reproductive phenotypes and follicular developmental stages using RT-qPCR. An erastin-induced ferroptosis model was established in sheep GCs, andFTH1function was evaluated through overexpression and interference experiments. Ferroptosis-related indicators, including ROS, C11-BODIPY 581/591, Fe2+, malondialdehyde (MDA), reduced glutathione (GSH), ferroptosis-associated genes, and GPX4 protein expression, were analyzed. Steroidogenic function was assessed by measuring the expression ofSTAR,CYP11A1,HSD17B1, and3β-HSD, as well as estradiol (E2) and progesterone (P4) secretion. RNA sequencing was performed to identify transcriptional changes associated withFTH1overexpression in erastin-treated GCs.FTH1expression was higher in ovaries from multiparous sheep and healthy follicles.FTH1overexpression alleviated erastin-induced ferroptosis by enhancing GPX4 expression and reducing Fe2+accumulation, ROS production, and lipid peroxidation, whereasFTH1knockdown aggravated ferroptosis damage. Furthermore,FTH1maintained steroidogenic function by promotingSTARexpression and preserving E2and P4synthesis under ferroptosis stress. Ferrostatin-1 (Fer-1) partially rescued GC viability and steroidogenic capacity, and attenuated erastin-induced apoptosis. Under erastin treatment, transcriptome analysis identified 297 differentially expressed mRNAs and 92 lncRNAs betweenFTH1-overexpressing GCs and the corresponding vector control. These differentially expressed transcripts represent candidate regulatory relationships that require further functional validation. Enrichment analysis highlighted cytokine signaling and ROS-related pathways, suggesting potential processes associated with the effects ofFTH1under these conditions. Collectively, these findings support thatFTH1protects sheep GCs against ferroptosis-induced injury and supports steroidogenic function, providing new insights into the role of iron homeostasis in follicular development.
✓ 已验证
DOI
高影响因子
eLife
·
2024
·
IF 6.4
Fangyan Wang,Xiujie Liu,Furong Huang,Yan Zhou,Xinyu Wang,Zhengyang Song,Sisi Wang,Xiaoting Wang,Dibang Shi,Gaoyi Ruan,Xiawei Ji,Eryao Zhang,Zenglin Tan,Yuqing Ye,Chuang Wang,Jesse Zhu,Wantie Wang
Hepatic ischemia/reperfusion injury (HIRI) is a common and inevitable factor leading to poor prognosis in various liver diseases, making the outcomes of current treatments in clinic unsatisfactory. Metformin has been demonstrated to be beneficial to alleviate HIRI in recent studies, however, the underpinning mechanism remains unclear. In this study, we found metformin mitigates HIRI-induced ferroptosis through reshaped gut microbiota in mice, which was confirmed by the results of fecal microbiota transplantation treatment but showed the elimination of the beneficial effects when gut bacteria were depleted using antibiotics. Detailedly, through 16S rRNA and metagenomic sequencing, we identified that the metformin-reshaped microbiota was characterized by the increase of gamma-aminobutyric acid (GABA) producing bacteria. This increase was further confirmed by the elevation of GABA synthesis key enzymes, glutamic acid decarboxylase and putrescine aminotransferase, in gut microbes of metformin-treated mice and healthy volunteers. Furthermore, the benefit of GABA against HIRI-induced ferroptosis was demonstrated in GABA-treated mice. Collectively, our data indicate that metformin can mitigate HIRI-induced ferroptosis by reshaped gut microbiota, with GABA identified as a key metabolite.
✓ 已验证
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.
✓ 已验证
DOI
PubMed
高影响因子
Frontiers in Pharmacology
·
2025
·
IF 4.8
Junhui Yu,Ningning Shao,Jianming Yang,Long Yang,Kaiwen Hong,Yuzhu Chen,Xiaoming Zhao,Hongzhi Yu,Tao Zhang,Jinrui Dong
Introduction Nonalcoholic steatohepatitis (NASH) is a chronic liver disease associated with oxidative stress and ferroptosis, leading to liver injury and fibrosis. Garlic, renowned for its antioxidant and hepatoprotective properties, is commonly used in traditional medicine. Ultrafine powder technology enhances the physicochemical properties of natural products, improving their bioavailability and efficacy. This study explores the protective effects of ultrafine garlic powder (UGP) on NASH and its underlying mechanisms. Methods In this study, UGP was prepared by high-speed particle collision technology and compared with traditional garlic powder (TGP). Results UGP exhibited a particle size (d(0.5) of approximately 4 μm) that is 30 times smaller than TGP, showing significantly smaller particle size and lower contact angle (UGP=59.775°vs TGP=83.545°). UGP also demonstrated improved solubility and dispersibility, along with an enrichment of key organosulfur compounds such as allicinAllicin, Alliin, SAC, and GSAC. In vitro, UGP significantly reduced palmitic acid-induced ROS production (n=4, p< 0.0001), prevented mitochondrial dysfunction (n=4, p=0.0035), and thereby reduced hepatic stellate cell activation. UGP lowered intracellular Fe2+ levels in hepatocytes from 68.72% to 34.48% (n=4) and significantly protected hepatocytes from erastin-induced ferroptosis (cell viability: UGP treatment 23.46% vs erastin stimulation 53.91%, n = 4, p <0.0001).In the acute liver fibrosis model induced by methionine- and choline-deficient diet supplemented with 60 kcal% fat (CDHF), UGP significantly improved liver histology. Compared to the model group, the liver/body weight ratio of mice was significantly restored (n=4, p<0.0001), and histopathological staining showed a substantial improvement in liver damage. Biochemically, UGP significantly reduced the levels of liver collagen, triglycerides, and cholesterol (n = 6, p < 0.0001). Fibrosis-related mRNA and pro-inflammatory mRNA expression were significantly decreased. Western blot results showed that UGP significantly inhibited the activation of p-ERK signaling. In the chronic liver fibrosis model induced by a diet with 60 kcal% fat (HFD), UGP demonstrated similar therapeutic effects. RNA-seq analysis revealed that UGP modulated key pathways, including fatty acid metabolism and the MAPK signaling pathway, and suppressed ROS production, further highlighting its therapeutic potential in NASH treatment. Discussion Taken together, these data suggest that UGP alleviates NASH by inhibiting hepatocyte ferroptosis and modulating ERK-dependent oxidative stress, supporting its potential as a therapeutic agent.
✓ 已验证
产品关联
DOI
PubMed
高影响因子
ANALYTICAL CHEMISTRY
·
2025
·
IF 6.7
Lu Li,Qinglin Fei,Xuwen Sun,Qiaochun Wang,Jianhua Su,Longyun Ye,Weiding Wu,Lifang Guo
Elucidating pathway-specific ferroptosis mechanisms is crucial for advancing our understanding of cell death regulation; however, this goal has been hindered by the persistent absence of reliable detection techniques and standardized analytical approaches. Mechanistically, ferroptosis is governed by the nexus between Glutathione Peroxidase 4 (GPX4) inactivation and lipid-peroxide-driven membrane destabilization, with cysteine (Cys) as a key regulator for GPX4 synthesis and ferroptosis trigger differentiation. Lipid peroxide accumulation elevates cytoplasmic viscosity, enabling the decryption of ferroptosis-trigger mechanisms by elucidating Cys-viscosity dynamics. For this, we engineer an innovative dual-parameter sensing platform: a conformationally flexible molecular scaffold with triple-emission viscosity sensitivity was functionalized with a Cys-reactive aldehyde group. This probe system features a fluorescence quenching mechanism and then sequentially restores red and blue fluorescence in the presence of Cys and high viscosity. Notably, while distinct ferroptosis pathways induce an observable viscosity increase, the Cys flux profiles exhibit pathway-specific signatures. Direct synthesis blockade displays a remarkable Cys fluctuation (Δ[Cys] = 20%, 4 h) compared to GPX4 inhibition (Δ[Cys] = 21%, 12 h), whereas overload iron demonstrates imperceptible variation (Δ[Cys] = 28%, 36 h latency). Furthermore, the evaluation of Cys-dependent ferroptosis in pancreatic cancer models uncovers therapy response mechanisms. This work highlights the key role of Cys and viscosity kinetics in ferroptosis initiation and execution phases, advancing the fundamental research and precise regulation of ferroptosis.
✓ 已验证
产品关联
DOI
PubMed
高影响因子
ACS Applied Nano Materials
·
2025
·
IF 5.5
Lin Li,Tiantian Lei,Kejing Wang,Yong Liu,Bingjun Sun,Lin Chen
Chemotherapy has been established as a standard therapeutic regimen for triple-negative breast cancer (TNBC). However, the efficacy of current therapeutic approaches remains suboptimal, primarily attributed to insufficient drug accumulation and the rapid development of chemoresistance. Thus, the rational design of drug delivery systems capable of triggering multimodal cell death pathways represents a promising strategy to combat TNBC. Ferroptosis emerges as a potent form of nonapoptotic cell death, showing great potential for tumor inhibition. The effective codelivery of chemotherapeutic drugs and ferroptosis activators provides potential ideas for the treatment of TNBC. Prodrug-based nanoassemblies have attracted tremendous attention in drug delivery, especially homodimeric prodrugs with ultrahigh drug loading. However, due to their symmetric structures, most homodimeric prodrugs exhibit poor self-assembly ability. Herein, two doxorubicin (DOX) homodimeric prodrugs were designed and coassembled with a GPX4 inhibitor (ML210). The incorporation of ML210 significantly promotes the stability of DOX nanoassemblies and improves the intracellular breakage of the DOX prodrug by regulating the GSH level. As a result, the ML210-driven doxorubicin homodimeric prodrug nanoassemblies exhibit high drug loading capacity, high self-assembly stability, and synergistic chemotherapy-ferroptosis effects. Our results present a viable approach to promote the self-assembly of homodimeric prodrugs while offering an efficient nanoplatform for TNBC treatment.
✓ 已验证
产品关联
DOI
高影响因子
KAOHSIUNG JOURNAL OF MEDICAL SCIENCES
·
2025
·
IF 3.1
Rui-Shi Wei,Yong-Ping Liu,Chun-Dong Gu,Shi-Lei Zhao,Li Feng,Jian-Rong Yu
Non-small cell lung cancer (NSCLC) is the most common type of lung cancer, with a 5-year survival rate of less than 20% and a high risk of recurrence despite advances in treatment. This study aimed to identify new therapeutic targets to increase the effectiveness of NSCLC treatments. We examined the role of USP54 in ferroptosis using an MTT assay and assessed the levels of reactive oxygen species (ROS), ferrous iron (Fe 2+ ), and malondialdehyde (MDA). To explore the underlying molecular mechanism, the intermolecular interactions was assessed using coimmunoprecipitation (Co-IP), chromatin immunoprecipitation (ChIP), and dual-luciferase reporter assays. We found that USP54 expression was reduced in NSCLC and that its overexpression inhibited NSCLC cell proliferation while inducing ferroptosis, as indicated by increased ROS, Fe 2+ , and MDA levels, along with changes in SLC7A11, GPX4, and ACSL4 expression. Additionally, USP54 mediated the deubiquitination of FOXA2, decreasing its degradation. And FOXA2 promoted ACSL4 transcription, which further induced ferroptosis in NSCLC cells. In conclusion, USP54 promotes ferroptosis and inhibits NSCLC progression by stabilizing FOXA2, which in turn activates ACSL4 transcription. This study provides a theoretical foundation for the development of therapies targeting USP54 or ACSL4 for NSCLC treatment.
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Scientific Reports
·
2025
·Vol. 15
·期 1
·1-14
·
IF 3.9
Zhang Yuxi,Zhan Junbiao,Qiu Zhen,Tian Hao,Lei Shaoqing,Huang Qin,Xue Rui,Sun Qian,Xia Zhongyuan
Myocardial cold ischemia/reperfusion (I/R) injury is an inevitable consequence of heart transplantation, significantly affecting survival rates and therapeutic outcomes. Growth Differentiation Factor 15 (GDF15) has been shown to regulate GPX4-mediated ferroptosis, playing a critical role in mitigating I/R injury. Meanwhile, verbascoside (VB), an active compound extracted from the herbaceous plant, has demonstrated myocardial protective effects. In this study, heart transplantation was performed using a modified non-suture cuff technique, with VB administered at a dose of 20 mg/kg/day via intraperitoneal injection for 3 days in vivo. In vitro, cardiomyocytes were pretreated with 50 µg/ml VB for 24 h. VB treatment significantly reduced histopathological injury, decreased myocardial injury markers, and inhibited ferroptosis and oxidative stress during myocardial cold I/R injury in vivo. In vitro experiments further demonstrated that GDF15 alleviates ferroptosis induced by hypoxic reoxygenation by upregulating GPX4. Therefore, it is concluded that VB preconditioning can effectively reduce ferroptosis induced by myocardial cold I/R after heterotopic heart transplantation, possibly through up-regulation of GDF15/GPX4/SLC7A11 pathway.
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Materials Today Bio
·
2025
·
IF 10.2
Shu-xian Liu,Jun-yu Zhang,Xiao-yan Zheng,Yong-zhong Du,Xiang-min Tong
Diffuse large B-cell lymphoma (DLBCL) is one of the most prevalent lymphomas, and can be classified as activated B-cell DLBCL (ABC-DLBCL) or germinal center B-cell DLBCL (GCB-DLBCL) according to molecular subtypes. Studies have shown that drug resistance is an important factor in its therapeutic failure. Tumor-specific drug delivery nanocarriers may be a promising strategy for the treatment of lymphoma. Herein, we developed a nanomedicine (RTX-DOX/DMF-Lip, RDDL) carrying the chemotherapeutic drugs doxorubicin (DOX) and dimethyl fumarate (DMF), and surface-modified with rituximab (RTX), which can recognize CD20 antigen when it comes into contact with the surface of a B-lymphoma cell. In the study, we found that DOX and DMF can be delivered to the tumor site precisely and demonstrate a potent synergistic anti-tumor effect. Once the nanomedicine was internalized, it induced apoptosis through ROS generation and the activation of caspase-3. Concurrently, DMF directly reduced the levels of glutathione (GSH) in tumor cells by inhibiting System Xc - , thereby resulting in impaired ROS detoxification and fostering an environment conducive to lipid peroxidation (LPO) and ferroptosis. Furthermore, the ROS generated by DOX synergistically propelled the process of ferroptosis, creating a potent therapeutic effect. These effects were validated in the GCB-DLBCL mouse model, where RDDL had a more potent killing effect compared to free drugs by striking SU-DHL-10 cells through a dual mechanism of apoptosis and ferroptosis, providing a new therapeutic strategy for the treatment of drug-resistant GCB-DLBCL.
✓ 已验证
产品关联
DOI
PubMed
高影响因子
CELL PROLIFERATION
·
2025
·
IF 5.6
Changsen Bai,Jialei Hua,Donghua Meng,Yue Xu,Benfu Zhong,Miao Liu,Zhaosong Wang,Wei Zhou,Liming Liu,Hailong Wang,Yang Liu,Lifang Li,Xiuju Chen,Yueguo Li
Glutaminase-1 (GLS1) has garnered considerable interest as a metabolic target in cancer due to its heightened involvement and activity. However, the precise fate of glutaminolysis catalysed by GLS1 in cancer cells remains elusive. We found that GLS1 knockout led to significant suppression of cancer cell proliferation, which can be reversed or partially restored by supplementation of glutamate or non-essential amino acids that can be converted into glutamate. The addition of spliceosomal KGA or GAC ameliorates cancer cell growth in vitro and in vivo, providing both simultaneously completely reverse the effect. The primary metabolic fate of glutamate produced through glutaminolysis in cancer cells is mainly used to produce glutathione (GSH) for redox homeostasis, not entering the tricarboxylic acid cycle or synthesising nucleotides. GSH monoethyl ester (GSH-MEE) effectively rescues the inhibition of cancer cell proliferation caused by GLS1 knockout. Deletion of GLS1 results in an elevation of reactive oxygen species (ROS) and malondialdehyde (MDA), a reduction of NADPH/NADP + ratio, and an augmented susceptibility of cells to ferroptosis. Glutathione Peroxidase 4 (GPX4) and GPX1 exhibit complementary roles in redox regulation, with GLS1 knockout promoting GPX4 degradation. Pharmacological inhibition of GLS1 synergises with GPX4 inhibitor to suppress tumour growth. Dual targeting of GPX4 and GPX1 presents a potent anti-cancer strategy. This metabolic mechanism facilitates a deeper comprehension of the abnormal glutamine metabolism in cancer cells, establishing a theoretical basis for the potential clinical utilisation of GLS1 inhibitors and presenting novel perspectives for advancing combinatorial therapeutic approaches.
✓ 已验证
产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）