EUROPEAN JOURNAL OF PHARMACOLOGY
·
2023
·
IF 5
Jiangbo Nie,Yuhang Ling,Mingchao Jin,Zhuo Chen,Wei Liu,Weiyun Shen,Tianshun Fang,Jianyou Li,Ying He
Osteosarcoma (OS) is a highly fatal bone tumor characterized by high degree of malignancy and early lung metastasis. Traditional chemotherapy fails in improving the efficacy and survival rate of patients with OS. Butyrate (NaBu) has been reported as a new antitumor drug for inhibiting proliferation and inducing apoptosis in various cancer cells. However, the effect of NaBu on the ferroptosis of osteosarcoma is still unknown. This study aimed to investigate whether NaBu promotes erastin-induced ferroptosis in OS cells and to uncover the underlying mechanism. Here, we found that NaBu significantly enhanced erastin-induced ferroptosis in vitro . Compared with the group that erastin used alonely, pre-treating with NaBu exacerbated erastin-meditated GSH depletion, lipid peroxidation, and mitochondrial morphologic changes in OS cells. In a subcutaneous OS model, NaBu combined with erastin significantly reduced tumor growth and increased the levels of 4-HNE. Mechanistically, NaBu downregulated SLC7A11 transcription via regulating ATF3 expression. Overexpression of ATF3 facilitated erastin to induce ferroptosis, while ATF3 knockdown attenuated NaBu-induced ferroptosis sensitivity. In conclusion, our findings revealed a previously unidentified role of NaBu in erastin-induced ferroptosis by regulating SLC7A11, suggesting that NaBu may be a potential therapeutic agent for OS treatment.
✓ 已验证
产品关联
DOI
PubMed
高影响因子
ACS Nano
·
2026
·
IF 17.3
Yilin Huang,Huan Ru,Chanlin Fang,Shanshan Di,You Weng,Mingrong Qian,Yuanxiang Jin
Abstract 6PPD, as an antioxidant in tire rubber, constitutes an emerging pollutant together with nanoplastics (NPs) widely present in the environment. This study explored the potential combined toxicity risk of 6PPD and 50 nm polystyrene nanoplastics (PS-NPs) to aquatic ecosystems. The study found that the presence of PS-NPs altered the physicochemical behavior of 6PPD and was associated with reduced cardiac accumulation of 6PPD and its oxidation product 6PPD-Q. The experiment showed that 6PPD activated the p53 signaling pathway by upregulating the expression of GRK5, thereby inhibiting the expression of SLC7A11 and GPX4, leading to increased ROS, iron overload, lipid peroxidation, and mitochondrial damage in zebrafish heart and rat cardiomyocytes (H9C2), thereby triggering ferroptosis. After coexposure of PS-NPs and 6PPD, physicochemical interactions between PS-NPs and 6PPD altered the colloidal state and environmental behavior of the mixture, while the cardiac levels of both 6PPD and 6PPD-Q were reduced, accompanied by weakened ferroptosis-related responses. This study revealed the cardiotoxic mechanism of 6PPD and the mitigation effect of PS-NPs after coexposure, providing a basis for environmental pollution risk assessment.
✓ 已验证
DOI
高影响因子
Advanced Science
·
2026
·
IF 14.1
Wenxin Huang,Yi Sun,Yanxin Wang,Haijun Yan,Xiaoping Yue,Weidong Wu,Xueyu Chen,Jinfang Zhang,Yanbing Lin,Qiong Lei,Nan Ji,Shuaishuai Xing,Liqin Zeng,Qingzheng Kang,Depeng Zhao,Geng Guo,Huidong Zhang
The pathogenesis of unexplained miscarriage (UM) is largely unclear. Environmental Zn pollution is widely present in various environments and inevitably ingested by pregnant women, which has shown reproductive toxicity. Disulfidptosis is a newly identified programmed cell death caused by excessive disulfide stress. Notably, the association, causation, and underlying mechanisms among Zn exposure, disulfidptosis, and unexplained miscarriage are completely unknown. In this study, based on two UM case-control groups, four ZnCl 2 -exposed mouse models, and a ZnCl 2 -exposed trophoblast Swan 71 cell model, we obtain a consistent conclusion that excessive Zn exposure causes disulfidptosis and thus induces miscarriage by up-regulating the GATA1/METTL1/SLC7A11 axis. In the mechanism, Zn exposure up-regulates GATA1 expression levels, which promotes GATA1-mediated METTL1 and SLC7A11 transcription. Meanwhile, Zn exposure also promotes METTL1-mediated m7G modification on SLC7A11 mRNA and thus increases SLC7A11 mRNA stability. Ultimately, Zn exposure up-regulates SLC7A11 expression levels at both transcription and post-transcription levels and thus causes disulfidptosis. Knockdown of murine Slc7a11, Gata1, or Mettl1, or supplement with NADPH suppresses mouse placental disulfidptosis and alleviates mouse miscarriage. This study not only discovers pathogenesis and biological mechanisms of Zn exposure-induced unexplained miscarriage but also provides potential targets, uncovering new health risk effects of Zn exposure in the environment-health field.
✓ 已验证
DOI
PubMed
高影响因子
CELLULAR SIGNALLING
·
2025
·
IF 3.7
Jiaoquan Chen,Hui Zou,Bihua Liang,Yeqing Gong,Shaoyin Ma,Runxiang Li,Jiacong Zeng,Chao Bi,Huilan Zhu
Drug resistance poses a significant challenge in the clinical management of melanoma, primarily driven by the hypoxic tumor microenvironment. This study aims to elucidate the molecular mechanisms underlying drug resistance in melanoma under hypoxic conditions. Exosomes were isolated from melanoma cells cultured under normoxic (Nor-exos) and hypoxic (Hypo-exos) environments. The proliferative capacity of tumor cells was assessed using CCK-8 and colony formation assays, while relevant molecular expressions were evaluated through qPCR, Western blotting, immunofluorescence, and immunohistochemistry. Additionally, mitochondrial damage was examined via transmission electron microscopy, and reactive oxygen species (ROS) levels were quantified using flow cytometry. Xenograft models further facilitated the investigation into the molecular mechanisms of drug resistance. Hypo-exos promote drug resistance in melanoma cells by inhibiting ferroptosis; mechanistically, Hypo-exos inhibiting p53 and OTUB1 expression through HIF-1α transfer. Furthermore, OTUB1 enhances SLC7A11 stability, thereby reducing ferroptosis levels and fostering drug resistance in melanoma. Our findings indicate that Hypo-exos inhibit ferroptosis to augment drug resistance in melanoma by delivering HIF-1α to modulate the p53/OTUB1/SLC7A11 axis. Exosomal HIF-1α may represent a promising biomarker and therapeutic target for addressing drug resistance in melanoma.
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Antioxidants
·
2025
·Vol. 14
·期 6
·698
·
IF 6.6
Ziyun Hu,Yuxin Li,Di Xu,Huihui Meng,Wenya Liu,Qian Xu,Benxing Yao,Junsong Wang
Ferroptosis, an iron-dependent form of regulated cell death characterized by lipid peroxidation, plays a crucial role in acetaminophen (APAP)-induced hepatotoxicity. While 4-octyl itaconate (4-OI) demonstrates protective effects against APAP toxicity, its molecular mechanisms remain to be fully elucidated. Through an innovative integration of untargeted metabolomics and pathway analysis, we unveil a novel dual mechanism by which 4-OI prevents APAP-induced ferroptosis. We discovered that 4-OI stabilizes SLC7A11 through OTUB1-mediated deubiquitination, thereby restoring cystine import and glutathione (GSH) synthesis. In addition, 4-OI activates the Nrf2 pathway, orchestrating a comprehensive antioxidant response by upregulating the key proteins involved in both glutathione metabolism and iron homeostasis, including GPX4, FTH1, FTL1, and FPN1. This coordinated action effectively prevents the accumulation of toxic iron and lipid peroxides. Our findings not only elucidate the protective mechanisms of 4-OI but also establish it as a promising therapeutic candidate for ferroptosis-related diseases through its unique ability to simultaneously modulate the SLC7A11-GPX4 antioxidant axis and iron homeostasis.
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Cancers
·
2022
·Vol. 14
·期 2
·345
·
IF 6.575
Hui Chen,Han Zhang,Lixing Cao,Jinling Cui,Xuan Ma,Chong Zhao,Shutao Yin,Hongbo Hu
Simple SummarySelenite, a representative inorganic form of selenium, is preferentially accumulated in tumors. The therapeutic potential of sodium selenite in tumors has received significant attention. However, the effect of sodium selenite in the treatment of established tumors is hampered by its systemic toxicities. In this study, we found selenite exerted a stronger lethality to the cancer cells under the condition of glucose limitation in vitro and an enhanced inhibitory effect on tumor growth when combined with intermittent fasting in vivo. In addition, this treatment showed no obvious toxicity to normal cells and mice. The findings of the present study provide an effective and practical approach for increasing the therapeutic window of selenite and imply that combination of selenite and fasting holds promising potential to be developed a clinically useful regimen for treating certain types of cancer.AbstractCombination of intermittent fasting and chemotherapy has been drawn an increasing attention because of the encouraging efficacy. In this study, we evaluated the anti-cancer effect of combination of glucose limitation and selenite (Se), a representative inorganic form of selenium, that is preferentially accumulated in tumors. Results showed that cytotoxic effect of selenite on cancer cells, but not on normal cells, was significantly enhanced in response to the combination of selenite and glucose limitation. Furthermore, in vivo therapeutic efficacy of combining selenite with fasting was dramatically improved in xenograft models of lung and colon cancer. Mechanistically, we found that SLC7A11 expression in cancer cells was up-regulated by selenite both in vitro and in vivo. The elevated SLC7A11 led to cystine accumulation, NADPH depletion and the conversion of cystine to cysteine inhibition, which in turn boosted selenite-mediated reactive oxygen species (ROS), followed by enhancement of selenite-mediated cytotoxic effect. The findings of the present study provide an effective and practical approach for increasing the therapeutic window of selenite and imply that combination of selenite and fasting holds promising potential to be developed a clinically useful regimen for treating certain types of cancer.Keywords:selenite;glucose limitation;SLC7A11;NADPH;ROS
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH
·
2026
·Vol. 45
·期 1
·153
·
IF 14.3
Wang Lifen,Xu Hongxia,Liu Tianyu,Zhu Dongliang,Chen Liping,Liu Tzu-ming,Lin Shuhai,Liu Xueyi,Feng Hao,Wang Li,Di Li-jun
Background Triple-negative breast cancer (TNBC) is characterized by aggressive clinical behaviour and frequent resistance to chemotherapy. While ferroptosis—an iron-dependent form of cell death driven by lipid peroxidation—holds promise as a therapeutic strategy, its efficacy is often limited by adaptive resistance mechanisms that remain incompletely understood. C-terminal binding protein (CtBP) is an oncogene associated with poor prognosis in TNBC; however, whether CtBP confers resistance to oxidative stress and ferroptosis, thereby contributing to its oncogenic function, remains unknown. Methods We utilized both in vitro cell lines and in vivo mouse models to investigate the role of CtBP in regulating oxidative stress and ferroptosis sensitivity. Integrative analyses, including transcriptomics, metabolomics, and clinical data interrogation, were employed to elucidate the mechanisms underlying CtBP-mediated resistance. Key mechanistic findings were further validated in clinical TNBC specimens using protein correlation analysis. Results We identified CtBP as a stress-inducible gene that is essential for ferroptosis resistance in TNBC. Mechanistically, CtBP promotes resistance by transcriptionally upregulating Prolyl 4-Hydroxylase Subunit Beta (P4HB). P4HB, localized to the endoplasmic reticulum (ER), functions as a chaperone to facilitate the correct folding and membrane maturation of SLC7A11, the catalytic subunit of the system xc - cystine/glutamate antiporter pivotal for glutathione (GSH) biosynthesis. We demonstrated that P4HB-mediated SLC7A11 maturation relies on its disulfide isomerase activity and ER retention signal (KDEL). Depletion of either CtBP or P4HB impaired SLC7A11 membrane trafficking, lead to accumulation of lipid peroxides and sensitization to ferroptosis. Conversely, P4HB overexpression restored SLC7A11 function and ferroptosis resistance in CtBP-deficient cells. Furthermore, significant positive correlations among CtBP, P4HB, and SLC7A11 expressions in clinical samples underscore the critical role of CtBP/P4HB/SLC7A11 axis in driving cancer aggressiveness. In vivo, targeting the CtBP/P4HB/SLC7A11 axis sensitized TNBC xenografts to the ferroptosis inducer RSL3, significantly suppressing tumor growth and lung metastasis. Conclusions This study identifies the CtBP/P4HB/SLC7A11 axis as a critical mediator of ferroptosis resistance in TNBC. These findings highlight this pathway as a potent therapeutic target to overcome resistance and enhance the efficacy of ferroptosis-inducing regimens in TNBC treatment.
✓ 已验证
DOI
高影响因子
ACS Biomaterials Science & Engineering
·
2025
·
IF 5.5
Juan Huang,Mingjing Yang,Xingyu Zhou,Jigang Luo,Xiaoxia Yan,Guanghui Lin,Shijie Li,Shihui Liu,Zhuoyue Song,Chunzhi Tang,Nenggui Xu,Tao Liu,Jian Liang
Drug repurposing has received increasing attention in the field of oncology drug development as an alternative strategy to de novo drug synthesis. Disulfiram (DSF) has a long history of clinical application in alcohol withdrawal, and recent studies have revealed that its metabolite diethyldithiocarbamate (DDTC) can be coordinated with copper ions in vivo to form Cu-DDTC complexes with anticancer activity. However, the insufficient in vivo stability of DSF remains a challenge. In this study, the nanomedicine Cu-BTC@DDTC with DDTC-Cu(I) chemical valence and polycrystalline structure was prepared by incorporation of DDTC into the nanosized metal–organic framework (MOF) Cu-BTC. The in vitro cellular evaluation results showed that Cu-BTC@DDTC exhibited high inhibition of tumor cell growth, migration, and invasion. Animal experiments on the xenograft tumor model further demonstrated the excellent antitumor activity and biosafety of Cu-BTC@DDTC, and the antitumor activity was found to be closely related to the regulation of the SLC7A11/GPX4 signaling pathway to induce ferroptosis. This study provides a feasible option for antitumor drug development based on a drug repurposing strategy.
✓ 已验证
产品关联
DOI
PubMed
高影响因子
FREE RADICAL RESEARCH
·
2025
·
IF 2.9
Doudou Lu,Ling Yuan,Zhaozhao Wang,Duojie Xu,Fandi Meng,Shumin Jia,Yahong Li,Weiqiang Li,Yi Nan
The prognosis of gastric cancer (GC) remains poor due to metastases and resistance to chemotherapy. Ferroptosis is a novel cell death regulation mode characterized by iron dependence and lipid peroxidation. Dioscin, a compound extracted from the Paris polyphylla rhizomes roots, has been shown to have an inhibitory effect on cancers. However, whether it induces ferroptosis to participate in anti-cancer metastasis remains unclear. The ability of gastric cancer cells to invade and migrate was evaluated by wound healing and transwell assays. Malondialdehyde (MDA), glutathione (GSH) assay kit, and dichlorofluorescin diacetate (DCFH-DA) fluorescent probes were used to detect ferroptosis in gastric cancer cells. The expression levels of glutathione peroxidase 4 (GPX4) and solute carrier family 7 member 11 (SLC7A11) were detected by quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot methods. The rescue assay was performed by adding Ferrostatin-1 (Fer-1) co-treatment to verify that Dioscin inhibited gastric cancer metastasis by participating in ferroptosis. Dioscin inhibited gastric cancer cells’ wound healing, migration, and invasion process. In addition, Dioscin increased the level of reactive oxygen species (ROS) and MDA while decreasing GSH level, and induced ferroptosis of gastric cancer cells. Fer-1, an inhibitor of ferroptosis, could reverse the effect of Dioscin. In terms of mechanism, Dioscin induced ferroptosis through SLC7A11/GPX4 axis and was involved in the regulation of inhibiting metastasis of gastric cancer. These results suggested that Dioscin was involved in anti-cancer metastasis by inducing ferroptosis.
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Scientific Reports
·
2025
·Vol. 15
·期 1
·1-17
·
IF 3.9
Chen Dongzhui,Yin Feifei,Yang Pin,Xia Wanrong,Huang Yi,Feng Yue,Yang Li,Lin Shuqiang,Zhang Qiuyue
Bronchopulmonary dysplasia (BPD) is one of the most common respiratory diseases in preterm infants. Studies have shown that ferroptosis is involved in the pathogenesis of BPD, and thioredoxin-interacting protein (TXNIP)-mediated oxidative stress also plays a role in its development. The solute carrier family 7 member 11 (SLC7A11)/glutathione peroxidase 4 (GPX4) signaling pathway is one of the key pathways regulating ferroptosis. This study aimed to investigate the mechanism by which TXNIP regulates SLC7A11/GPX4 pathway-mediated ferroptosis in BPD. Mice were randomly divided into ten treatment groups: Air, Hyperoxia, Hyperoxia + RSL3, Hyperoxia + Ferrostatin-1, Hyperoxia + Ad-shNC, Hyperoxia + Ad-shTXNIP, Hyperoxia + Ad-vector, Hyperoxia + Ad-TXNIP, Hyperoxia + Ad-shSLC7A11, and Hyperoxia + Ad-shTXNIP + Ad-shSLC7A11. Lung tissues were collected for hematoxylin and eosin (H&E) staining to observe pathological changes, and transmission electron microscopy (TEM) was used to examine mitochondrial morphology. Real-time quantitative polymerase chain reaction (qPCR) was performed to measure the mRNA expression of TXNIP, SLC7A11, and GPX4. Western blotting was used to analyze the protein levels of TXNIP, SLC7A11, and GPX4. GPX4 activity was determined using an enzyme-linked immunosorbent assay (ELISA). Additionally, glutathione (GSH), malondialdehyde (MDA), and ferrous iron (Fe 2+ ) levels in lung tissues were measured using corresponding detection kits. H&E staining and TEM confirmed successful modeling of lung injury after hyperoxia. MDA and Fe 2+ increased, GSH decreased, and GPX4 activity declined after hyperoxia. TXNIP mRNA and protein were upregulated by hyperoxia, while SLC7A11 and GPX4 were downregulated. Ferroptosis activation exacerbated lung injury, whereas inhibition alleviated it. TXNIP overexpression using adenovirus serotype 5 (Ad5) aggravated ferroptosis in BPD, and this was ameliorated by TXNIP knockdown. Knockdown of the upstream signal SLC7A11 increased ferroptosis in BPD, and simultaneous knockdown of TXNIP and SLC7A11 reversed the ferroptosis reduction. In conclusion, in the BPD model, TXNIP expression was increased, and TXNIP promoted ferroptosis by downregulating the SLC7A11/GPX4 pathway. These findings suggest that gene therapy targeting TXNIP knockdown using adenovirus as a vector may serve as a therapeutic strategy for BPD.
✓ 已验证
DOI
PubMed
高影响因子
LIFE SCIENCES
·
2026
·
IF 5.1
Pan Huang,Kexin Zhang,Ying Chen,Jiaxin Cheng,Shuangshuang Yang,Lin Shi,Yajuan Wang,Qin Zhang
Elevated homocysteine (Hcy) is an independent risk factor for hypertension, and kidney is an important organ for Hcy metabolism and blood pressure regulation, and its damage is closely related to the process of hypertension. Recent evidence suggests that ferroptosis, an oxidative stress-related form of cell death, contributes significantly to hypertensive organ damage. However, whether Hcy aggravates renal injury in H-type hypertension by destroying renal hydrogen sulfide (H 2 S) metabolism and driving ferroptosis is still lack of direct evidence. In this study, the H-type hypertensive rat model induced by high methionine diet combined with HK-2 cell model was studied. We observed a significant increase in blood pressure and plasma Hcy in the Hcy group, accompanied by renal dysfunction and renal tubular injury. Specifically, in the renal tissue of Hcy group rats, the levels of KIM-1, Fe 2+ and malondialdehyde (MDA) were increased, glutathione/glutathione disulfide (GSH/GSSG) ratio decreased, SLC7A11 expression was down-regulated, and GPX4 activity was inhibited. Concurrently, H 2 S levels and cystathionine-beta-synthase (CBS) activity were decreased. In vitro experiments using HK-2 cells confirmed that Hcy could down-regulate the expression of CBS, cystathionine-gamma-lyase (CSE), SLC7A11, GPX4 and GSH/GSSG ratio, and up-regulate MDA and reactive oxygen species (ROS) levels. Treatment with H 2 S donor (NaHS) or ferroptosis inhibitors (Ferrostatin-1, Fer-1) could rescue these changes. Collectively, our results demonstrate that high Hcy promotes hypertension by suppressing endogenous H 2 S generation, downregulating the SLC7A11/GPX4 signaling axis, and inducing ferroptosis. These findings reveal a new mechanism by which Hcy aggravates hypertension by inhibiting H 2 S synthesis and inducing ferroptosis.
✓ 已验证
产品关联
DOI
PubMed
高影响因子
LANGMUIR
·
2026
·
IF 4.4
Li Sen,Wang Wentao,Chen Yizhang,Shao Qiuze,Yang Zhaoqi,Hua Dong
Non-small-cell lung cancer (NSCLC) is a lethal malignant
tumor
worldwide. Although ferroptosis offers a promising route for curcumin-mediated
non-small-cell lung cancer therapy, its efficacy is often constrained
by the robust antioxidant defense maintained by the SLC7A11/GSH/GPX4
axis, which continuously sustains cystine uptake, glutathione biosynthesis,
and GPX4-dependent lipid peroxide detoxification, thereby maintaining
cellular homeostasis. Herein, we developed a glutathione-responsive
metal–organic framework nanoplatform for the co-delivery of
curcumin and a GPX4-targeting antisense oligonucleotide (ASO). After
cellular internalization, the disulfide-bearing framework underwent
GSH-triggered disassembly, enabling synchronized release of curcumin
and ASO while depleting the intracellular GSH. Released curcumin increased
ROS accumulation and disturbed redox homeostasis, whereas ASO silenced
GPX4 expression to concurrently disable the antioxidant defense. Flow
cytometry and Western blot assays confirmed significant ROS accumulation
and SLC7A11 downregulation, which were detailed by molecular dynamics
simulations with putative binding modes. Furthermore, the nanocomposite
demonstrated robust anticancer effects in 3D multicellular tumor spheroids
with a promoted oxidative imbalance. Taken together, this coordinated
intervention disrupted the SLC7A11/GSH/GPX4 antioxidant axis, amplified
lipid peroxidation, impaired mitochondrial function, and ultimately
enhanced ferroptotic vulnerability.
✓ 已验证
产品关联
DOI
高影响因子
危险品化学品经营许可证（带存储）