CELL
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2025
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IF 42.5
Nan Zhou,Jingzhi Chen,Meiqin Hu,Na Wen,Weijie Cai,Ping Li,Liding Zhao,Yaping Meng,Dongdong Zhao,Xiaotong Yang,Siyu Liu,Fangqian Huang,Cheng Zhao,Xinghua Feng,Zikai Jiang,Enjun Xie,Hongxu Pan,Zhidong Cen,Xinhui Chen,Wei Luo,Beisha Tang,Junxia Min,Fudi Wang,Junsheng Yang,Haoxing Xu
Lysosomes maintain an acidic pH of 4.5–5.0, optimal for macromolecular degradation. Whereas proton influx is produced by a V-type H + ATPase, proton efflux is mediated by a fast H + leak through TMEM175 channels, as well as an unidentified slow pathway. A candidate screen on an orphan lysosome membrane protein (OLMP) library enabled us to discover that SLC7A11, the protein target of the ferroptosis-inducing compound erastin, mediates a slow lysosomal H + leak through downward flux of cystine and glutamate, two H + equivalents with uniquely large but opposite concentration gradients across lysosomal membranes. SLC7A11 deficiency or inhibition caused lysosomal over-acidification, reduced degradation, accumulation of storage materials, and ferroptosis, as well as facilitated α-synuclein aggregation in neurons. Correction of abnormal lysosomal acidity restored lysosome homeostasis and prevented ferroptosis. These studies have revealed an unconventional H + transport conduit that is integral to lysosomal flux of protonatable metabolites to regulate lysosome function, ferroptosis, and Parkinson’s disease (PD) pathology.
研究领域:
细胞生物学
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医学
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神经科学
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DOI
PubMed
高影响因子
OTOLOGY & NEUROTOLOGY
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2024
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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.
研究领域:
耳科学
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细胞生物学
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分子生物学
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DOI
高影响因子
PHYTOMEDICINE
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2025
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IF 8.3
Yu Liu,Honglin Chen,Kun Chen,Qi Shang,Feng Lin,Peng Zhang,You Zhang,Weicheng Qin,Huiwen Liu,Weiyu Qiu,Xingda Chen,Yan Gong,Yixuan Jiang,Yuzhuo Zhang,Jiahui He,Wenhua Zhao,Hui Ren,Gengyang Shen,Xiaobing Jiang
Background Skeletal muscle atrophy, which is a debilitating condition exacerbated by estrogen deficiency, lacks effective therapeutic interventions. Although ferroptosis (an iron-dependent form of cell death driven by lipid peroxidation) has emerged as a contributor to muscle degeneration, its regulatory mechanisms remain poorly defined. In this study, we identified luteolin, which is a natural flavonoid, as a potent inhibitor of ferroptosis that mitigates estrogen deficiency-induced muscle atrophy by targeting SLC7A11. Purpose The aim of this study was to investigate the role of ferroptosis in the anti-muscle atrophy effects of luteolin. Methods Via database screening, luteolin was identified as a potential drug for improving muscle atrophy, and the promotion of C2C12 myogenic differentiation by luteolin was detected by using immunofluorescence (IF), quantitative reverse transcription PCR (RT-qPCR) and western blot (WB). The mechanism of luteolin-mediated ferroptosis in muscle atrophy was confirmed by RNA-seq, transmission electron microscopy (TEM), and GSH, MDA, SOD and Fe 2+ assays. Molecular docking, molecular dynamics simulation, surface plasmon resonance (SPR), cellular thermal shift assay (CETSA), drug affinity responsive target stability (DARTS) and siRNA-mediated gene knockout were applied to validate the notion that the mechanism of luteolin treatment of muscle atrophy involves target binding to SLC7A11. In addition, this study confirmed the role of luteolin in ameliorating muscle atrophy via the modulation of the SLC7A11-mediated ferroptosis pathway in vivo . Finally, the effect of luteolin on the myogenic differentiation of HsKMCs was investigated. Results Luteolin promotes myogenic differentiation and significantly inhibits myotube atrophy, with the main mechanism of these effects involving the direct binding of luteolin to the SLC7A11 protein to inhibit the occurrence of ferroptosis. We confirmed that luteolin can inhibit ferroptosis in muscle tissue and improve the loss of muscle mass and strength due to muscle atrophy in vivo . In addition, luteolin significantly inhibited myotube atrophy in HsKMCs and promoted their myogenic differentiation by modulating the SLC7A11-mediated ferroptosis. Conclusions Our findings demonstrate that luteolin regulates myogenesis and prevents muscle atrophy through binding to SLC7A11 and subsequently inhibiting ferroptosis. This study elucidates the critical role of the SLC7A11-ferroptosis axis in preserving muscle physiology during atrophy, while identifying luteolin as a therapeutic agent capable of targeting SLC7A11 to suppress ferroptosis and alleviate muscle atrophy.
研究领域:
医学
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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
EUROPEAN JOURNAL OF PHARMACOLOGY
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2023
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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.
研究领域:
肿瘤学
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分子生物学
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细胞生物学
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DOI
PubMed
高影响因子
BRAIN RESEARCH BULLETIN
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2025
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IF 3.7
Qiyu Yang,Chunyan Wang,Jingwei Cao,Zhanbin Tang,Shurong Duan
Intracerebral hemorrhage (ICH) is associated with the highest rates of mortality and residual disability. To date, effective treatments to delay or prevent ICH are still lacking. Multiple forms of neuronal cell death have been discovered following ICH, including apoptosis, necrosis, autophagy, and ferroptosis. Aldo-keto reductase family 1 member C1 (AKR1C1) has been identified to act as a protective factor in ferroptosis. However, whether AKR1C1 was involved in the development of ICH was unknown. In this study, the left cerebral striatum of the Sprague-Dawley rat was injected with collagenase type IV to induce an in vivo model. Primary rat cortical neurons treated with oxygen hemoglobin (OxyHb) were applied to as an in vitro model. AKR1C1 was found to be downregulated and immunoreactivity colocalized with NeuN-positive neurons in the perihematomal region. Rats injected with lentiviral particles overexpressing AKR1C1 showed the reduction of cerebral hematoma and the remission of blood-brain barrier disruption. Moreover, AKR1C1 upregulation repressed cell apoptosis and ferroptosis induced by ICH through downregulating the expression of pro-apoptotic factors, inhibiting iron accumulation and lipid peroxidation, along with increasing the expression of solute carrier family 7 member 11 (SLC7A11) and glutathione peroxidase 4 (GPX4). The results of in vitro assays were consistent with results from the in vivo . Mechanistically, P53 overexpression augmented the cellular damage in OxyHb-stimulated neurons when AKR1C1 was overexpressed. Taken together, AKR1C1 improves ICH injury by inhibiting neuronal cell death via negatively regulating P53 expression and affecting the SLC7A11/GPX4 pathway.
研究领域:
神经科学
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分子生物学
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DOI
PubMed
高影响因子
Scientific Reports
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2025
·Vol. 15
·期 1
·1-14
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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.
研究领域:
心血管病学
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药理学
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移植学
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产品关联
DOI
PubMed
高影响因子
Frontiers in Cell and Developmental Biology
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2021
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IF 6.684
Zhu Yiming,Zhang Chihao,Huang Mingzhe,Lin Jiayun,Fan Xiao,Ni Tao
Hepatic stellate cells (HSCs) are activated by inflammatory mediators to secrete extracellular matrix for collagen deposition, leading to liver fibrosis. Ferroptosis is iron- and lipid hydroperoxide-dependent programmed cell death, which has recently been targeted for inhibiting liver fibrogenic processes. Tripartite motif-containing protein 26 (TRIM26) is an E3 ubiquitin ligase that functions as a tumor suppressor in hepatocellular carcinoma, while little is known about its function in liver fibrosis. In the present study, the differential expression of TRIM26 in normal and fibrotic liver tissues was examined based on both online databases and specimens collected from patient cohort. The effects of TRIM26 on HSCs ferroptosis were examined in vitro through evaluating cell proliferation, lipid peroxidation, and expression of key ferroptosis-related factors. In vivo function of TRIM26 in liver fibrosis was examined based on CCl4-induced mice model. We found that TRIM26 was downregulated in fibrotic liver tissues. The overexpression of TRIM26 inhibited HSCs proliferation, promoted lipid peroxidation, manipulated ferroptosis-related factor expressions, and counteracted the effect of iron inhibitor deferoxamine. Moreover, TRIM26 physically interacted with solute carrier family-7 member-11 (SLC7A11), a critical protein for lipid reactive oxygen species (ROS) scavenging, and mediated its ubiquitination. In addition, TRIM26 overexpression induced HSCs ferroptosis and mitigated CCl4-induced liver fibrosis in mice. In conclusion, TRIM26 promotes HSCs ferroptosis to suppress liver fibrosis through mediating the ubiquitination of SLC7A11. The TRIM26-targeted SLC7A11 suppression can be a novel therapeutic strategy for liver fibrosis.
研究领域:
分子生物学
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细胞生物学
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肝病学
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产品关联
DOI
PubMed
高影响因子
INTERNATIONAL IMMUNOPHARMACOLOGY
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2023
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IF 5.6
Lijuan Ma,Xueqi Liu,Mengya Zhang,Lang Zhou,Ling Jiang,Li Gao,Xian Wang,Yuebo Huang,Hanxu Zeng,Yonggui Wu
The pathophysiological mechanism of acute kidney injury (AKI) is complicated, and effective drugs are still lacking. Ferroptosis is a newly discovered regulatory cell death mode characterized by the lethal accumulation of iron and reactive oxygen species-(ROS-)-dependent lipid hydroperoxides. In recent years, ferroptosis has been confirmed to be involved in the progression of AKI. Paeoniflorin (PF) is a traditional Chinese medicine that has protective effects on a variety of kidney diseases including AKI. However, the mechanism by which PF attenuates AKI is unclear. We detected that PF attenuated serum biochemical markers, histological damage, ferroptosis and inflammation in a dose-dependent manner in a mouse AKI model with bilateral renal artery ischemia–reperfusion (IR). Hypoxia-reoxygenation (HR)-induced ferroptosis and inflammation was also inhibited by PF in human renal tubular epithelial cells (HK2). RNA sequence analysis revealed that PF inhibited ferroptosis in HK2 cells by upregulating Slc7a11 in the glutathione pathway after HR treatment. PF failed to further protect cells with specific knockdown of Slc7a11 from ferroptosis under HR conditions. Consequently, these data indicated that PF prevention of ferroptosis in AKI requires dependence on Slc7a11. This study provided a scientific basis for the clinical search for drugs to prevent IR induced AKI.
研究领域:
药理学
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肾病学
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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
Cancers
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2022
·Vol. 14
·期 2
·345
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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
研究领域:
肿瘤学
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药理学
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细胞生物学
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产品关联
DOI
PubMed
高影响因子
Materials Today Bio
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2025
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IF 10.2
Qiang Zhang,Tuo Wang,Junyu Ren,Yanru Guo,Ziyi Yin,Chenrui Zhang,Honglin Fan,Yinting Ren,Junlong Da,Narisu Hu
Oral ulcers, a prevalent mucosal disorder with high recurrence rates, remain challenging to treat due to the oral cavity’s dynamic environment and the multifactorial nature of ulcer progression. Here, we report a multifunctional microneedle (MN) patch loaded with astragalus polysaccharide (APS-MN) that integrates rapid mucosal penetration, reactive oxygen species (ROS) scavenging, and ferroptosis inhibition to accelerate ulcer healing. Unlike conventional MN systems reliant on synthetic drugs or prolonged dissolution, APS-MN leverages the natural antioxidant and immunomodulatory properties of APS-a traditional Chinese medicine-derived polysaccharide-enabling complete drug release within 2 minutes and targeted delivery to ulcer bases. In vitro and in vivo studies demonstrate that APS-MN promotes M2 macrophage polarization, suppresses pro-inflammatory cytokines (TNF-α, IL-1β), and inhibits ferroptosis via the Nrf2/HO-1/SLC7A11 axis, achieving 88.2% wound closure in rats within 6 days. Notably, this work combined herbal polysaccharides with MN technology for oral ulcer therapy, offering a biocompatible, non-invasive alternative to corticosteroids and antibiotics. The rapid dissolution, dual antioxidant/anti-ferroptotic action, and scalability of APS-MN position it as a transformative platform for managing recurrent oral ulcers and other redox-imbalanced mucosal diseases.
研究领域:
药学
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生物医学工程
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免疫学
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产品关联
DOI
PubMed
高影响因子
Journal of Advanced Research
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2024
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IF 11.4
Yi Zhao,Xue-Qi Wang,Rui-Qi Liu,Fu-Wei Jiang,Jia-Xin Wang,Ming-Shan Chen,Hao Zhang,Jia-Gen Cui,Yuan-Hang Chang,Jin-Long Li
Introduction Phthalates exposure is a major public health concern due to the accumulation in the environment and associated with levels of testosterone reduction, leading to adverse pregnancy outcomes. However, the relationship between phthalate-induced testosterone level decline and ferroptosis remains poorly defined. Objectives Herein, we aimed to explore the mechanisms of phthalates-induced testosterone synthesis disorder and its relationship to ferroptosis. Methods We conducted validated experiments in vivo male mice model and in vitro mouse Leydig TM3 cell line, followed by RNA sequencing and metabolomic analysis. We evaluated the levels of testosterone synthesis-associated enzymes and ferroptosis-related indicators by using qRT-PCR and Western blotting. Then, we analyzed the lipid peroxidation, ROS, Fe 2+ levels and glutathione system to confirm the occurrence of ferroptosis. Results In the present study, we used di (2-ethylhexyl) phthalate (DEHP) to identify ferroptosis as the critical contributor to phthalate-induced testosterone level decline. It was demonstrated that DEHP caused glutathione metabolism and steroid synthesis disorders in Leydig cells. As the primary metabolite of DEHP, mono-2-ethylhexyl phthalate (MEHP) triggered testosterone synthesis disorder accompanied by a decrease in the expression of solute carri1er family 7 member 11 (SLC7A11) protein. Furthermore, MEHP synergistically induced ferroptosis with Erastin through the increase of intracellular and mitochondrial ROS, and lipid peroxidation production. Mechanistically, overexpression of SLC7A11 counteracts the synergistic effect of co-exposure to MEHP-Erastin. Conclusion Our research results suggest that MEHP does not induce ferroptosis but synergizes Erastin-induced ferroptosis. These findings provide evidence for the role of ferroptosis in phthalates-induced testosterone synthesis disorder and point to SLC7A11 as a potential target for male reproductive diseases. This study established a correlation between ferroptosis and phthalates cytotoxicity, providing a novel view point for mitigating the issue of male reproductive disease and “The Global Plastic Toxicity Debt”.
研究领域:
毒理学
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生殖生物学
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分子生物学
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药理学
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产品关联
DOI
PubMed
高影响因子
Heart Lung and Circulation
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2025
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IF 2.2
Dan-Qing Duan,Ming-Rui Li,Li-Qun Lu,Bi-Feng Yao,Lin-Lu Huang,Xiu-Ju Luo,Jun Peng
Background & Aim Ferroptosis is an iron-dependent cell death and contributes to myocardial ischaemia/reperfusion (I/R) injury. Downregulation of glutathione peroxidase 4 (GPX4) is a key factor to accelerate ferroptosis, but the underlying mechanisms are not fully elucidated. Solute carrier family 7A member 11 (SLC7A11) plays a key role in maintaining the normal level of GPX4, and its transcription is suppressed by p53, whose level is controlled by spermatogenesis-associated protein 2 (SPATA2)/cylindromatosis (CYLD) pathway in a de-ubiquitination-dependent way. This study aims to explore whether SPATA2/CYLD pathway promotes myocardial ferroptosis in rat hearts after I/R through p53-dependent inhibition of SLC7A11. Methods The rat hearts were subjected to 1 h-ischaemia plus 3 h-reperfusion to establish a myocardial I/R injury model, and H9c2 cells were subjected to 8 h-hypoxia plus 12 h-re-oxygenation (H/R) to mimic myocardial I/R injury in vitro. Results Both the rat hearts and the cultured cardiomyocytes showed elevated levels of SPATA2 and CYLD, concomitant with the increased p53 levels and the enhanced interaction between SPATA2 and CYLD; these phenomena were reversed by knockdown of SPATA2. Mechanistically, knockdown of SPATA2 restored the ubiquitination of p53 and decreased p53 level in the H/R-treated cardiomyocytes, accompanied by increases in the levels of SLC7A11 and GPX4, and reduction of ferroptosis. Furthermore, suppression of SPATA2 by lurasidone, a predicted inhibitor of SPATA2, in the I/R-treated rat hearts also achieved similar results. Conclusion SPATA2/CYLD pathway-dependent de-ubiquitylation of p53 promotes ferroptosis in rat heart after I/R through a mechanism involving suppression of SLC7A11.
研究领域:
分子生物学
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心血管医学
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细胞信号传导
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产品关联
DOI
PubMed
高影响因子
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