FOOD AND CHEMICAL TOXICOLOGY
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2022
·
IF 5.572
Hui Chen,Lixing Cao,Kai Han,Han Zhang,Jinling Cui,Xuan Ma,Shuang Zhao,Chong Zhao,Shutao Yin,Lihong Fan,Hongbo Hu
Patulin (PAT) is a common food-borne mycotoxin with diverse toxic effects including nephrotoxicity . The induction of oxidative stress is suggested to be a key mechanism contributed to toxicities of PAT. Reduced glutathione (GSH), a sulfhydryl-containing tripeptide , is a key reason for PAT-mediated oxidative stress. Cystine/glutamate antiporter (system x c − )-mediated cystine uptake plays a critical role in maintaining redox balance via promoting GSH biosynthesis. In this study, we addressed if GSH reduction by PAT was associated with inhibition of system x c − -mediated GSH biosynthesis. Results showed that PAT significantly decreased activity of SLC7A11, a core subunit of system x c − , through activating AMPK-mediated formation of beclin1-SLC7A11 complex. Furthermore, PAT promoted ferroptosis induced by a known ferroptosis inducer RSL3 in normal renal cells, and exacerbated folic acid-induced nephrotoxicity in a mouse model of acute kidney injury . The findings of the present study provide new insights into PAT-induced kidney toxicity, and implicate that patients with ferroptosis-associated diseases maybe more susceptible to PAT.
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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分子生物学
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DOI
PubMed
高影响因子
FEBS Journal
·
2021
·Vol. 289
·期 7
·1968-1983
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IF 5.542
Ting-Ting Wei,Meng-Yuan Zhang,Xin-Hua Zheng,Tian-Hua Xie,Wenjuan Wang,Jian Zou,Yan Li,Hong-Ying Li,Jiping Cai,Xiaolu Wang,Jianxin Tan,Xusheng Yang,Yong Yao,Lingpeng Zhu
Retinal pigment epithelium (RPE) cell damage is implicated in the pathogenesis of age-related macular degeneration (AMD). An increase of interferon-γ (IFN-γ) levels was observed in patients with AMD, but whether inflammatory factors are causally related to AMD progression is unclear. Here, we demonstrate a direct causal relationship between IFN-γ and RPE cell death. IFN-γ induced human retinal pigment epithelial cell (ARPE-19) death accompanied by increases in Fe 2+ , reactive oxygen species, lipid peroxidation, and glutathione (GSH) depletion, which are main characteristics of ferroptosis. Mechanistically, IFN-γ upregulates the level of intracellular Fe 2+ through inhibiting Fe 2+ efflux protein SLC40A1 and induces GSH depletion by blocking cystine/glutamate antiporter, System xc-. At the same time, treatment with IFN-γ decreases the level of glutathione peroxidase 4 (GPx4), rendering the cells more sensitive to ferroptosis. JAK1/2 and STAT1 inhibitors could reverse the reduction of SLC7A11, GPx4 and GSH expression induced by IFN-γ, indicating IFN-γ induces ARPE-19 cell ferroptosis via activation of the JAK1-2/STAT1/SLC7A11 signaling pathway. The above results were largely confirmed in IFN-γ-treated mice in vivo . Finally, we used sodium iodate (NaIO 3 )-induced retinal degeneration to further explore the role of ferroptosis in AMD in vivo . Consistent with the role of IFN-γ, treatment with NaIO 3 decreased SLC7A11, GPx4 and SLC40A1 expressions. NaIO 3 -induced RPE damage was accompanied by increased iron, lipid peroxidation products (4-hydroxynonenal, malondialdehyde), and GSH depletion, and ferroptosis inhibitors could reverse the above phenomenon. Taken together, our findings suggest that inhibiting ferroptosis or reducing IFN-γ may serve as a promising target for AMD.
研究领域:
眼科学
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细胞生物学
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分子生物学
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病理学
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DOI
PubMed
高影响因子
JOURNAL OF DRUG DELIVERY SCIENCE AND TECHNOLOGY
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2024
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IF 4.5
Yaru Li,Qian Yang,Lanlan Fan,Fang Liu,Yaqi Shang,Baoxin Zhang,Zheng Wang,Yanjun Zhao
Ovarian cancers (OC) often resist current standard chemotherapy because of the cancer heterogeneity and over-expression of an anti-apoptotic protein, myeloid cell leukemia-1 (MCL-1). The heterogeneous OC shows impaired redox homeostasis and relies heavily on glutathione peroxidase 4 to eliminate toxic lipid peroxides. Therefore, integrated apoptosis and ferroptosis therapy is promising for OC management. The current work reports a liposomal nanosystem for apoptotic and ferroptotic OC therapy. Simvastatin (Sim) and vorinostat (Saha) were selected as the pleiotropic model drugs. The successive release of Saha and Sim from liposomes enabled the sequential amplification of MCL-1 by Saha, and then MCL-1 inhibition by Sim. Such a strategy could potently induce apoptosis in a human OC cell line (SKOV3), as indicated by increased intracellular cytochrome c concentration, caspase 3/9 activity, and the extent of apoptosis. Besides, Saha played multiple roles in cell death. It could induce cell cycle arrest at the G 2 /M phase and apoptosis. Saha also inhibited the glutamate-cystine transporter (SLC7A11) and provoked ferroptosis, which was corroborated by the depletion of glutathione, reduced nicotinamide adenine dinucleotide phosphate, and boost of lipid peroxides and malondialdehyde in SKOV3 cells. The current work integrated the “sequential amplification and inhibition of MCL-1 target” concept with combinational apoptosis and ferroptosis OC therapy, which might offer a new approach for managing resistant OC and other malignant diseases.
研究领域:
肿瘤学
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药学
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细胞生物学
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纳米技术
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高影响因子
Cell Death Discovery
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2025
·Vol. 11
·期 1
·1-16
·
IF 7
Liang Xue,Tian Ruofei,Li Ting,Wang Hao,Qin Yifei,Qian Meirui,Fan Jing,Wang Dan,Cui Hong-Yong,Jiang Jianli
Pancreatic cancer exhibits high mortality rates with limited therapeutic options. Emerging evidence suggests that the ketogenic diet may act as adjuvant therapy by triggering ferroptosis in cancer cells, though the underlying molecular mechanisms remain unclear. This study aims to investigate the molecular mechanisms linking ketogenic metabolism and ferroptosis, with an emphasis on key regulatory proteins. We demonstrated that pancreatic adenocarcinoma (PAAD) tissues significantly enhanced ketogenic and ferroptosis phenotypes compared to normal tissues, both correlating with poorer patient prognosis. These phenotypes showed strong interdependence mediated by CAV1. In the pancreatic tumor microenvironment, CAV1 was predominantly expressed in tumor cells. Through in vitro cell experiments, we clarified that Na-OHB downregulated CAV1 expression in pancreatic cancer cells, inhibiting the transcription of the CAV1/AMPK/NRF2 downstream ferroptosis-protective genes SLC7A11 and SLC40A1. Additionally, we demonstrated the interaction between CAV1 and SLC7A11 molecules; when CAV1 was downregulated, it affected the stability of SLC7A11, leading to the ubiquitination and degradation of the translated SLC7A11 protein. Through these dual mechanisms, Na-OHB caused Fe 2+ overload, lipid peroxidation accumulation, and oxidative stress in pancreatic cancer cells, ultimately triggering ferroptosis. In ketogenic diet-fed tumor-bearing mouse models, we also observed a significant increase in lipid peroxidation and other related biomarkers, while CAV1 and SLC7A11 levels were markedly decreased compared to the normal diet group. Our findings identify CAV1 as a pivotal molecular link between ketogenic metabolism and ferroptosis in pancreatic cancer. The multi-level regulatory axis involving CAV1-mediated transcriptional regulation and post-translational modifications provides mechanistic insights into ketogenic diet-induced ferroptosis, suggesting potential therapeutic targets for pancreatic cancer adjuvant treatment.
研究领域:
肿瘤学
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分子生物学
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营养学
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DOI
PubMed
高影响因子
Advanced Healthcare Materials
·
2025
·
IF 9.6
SiJia Lin,Lin Wang,Xue Dong,ZiYi Wang,Jin Cao,Xueyong Qi,Lin Wu,Jing Zhang,Song Shen
Ferroptosis is a regulated cell death pathway driven by the iron-dependent accumulation of reactive oxygen species (ROS) and lipid hydroperoxides. A major factor limiting the effectiveness of ferroptosis induction is the antioxidant activity of glutathione peroxidase 4 (GPX4). Herein, we reported SLC7A11-targeting proteolysis targeting chimeras (PROTACs) to deplete GPX4 and to augment oxidative stress within cancer cells. A bifunctional PROTAC, namely dSLC7A11, ws designed by conjugating the SLC7A11 inhibitor sulfasalazine to the CRBN ligand pomalidomide via an alkyl linker. The rational designed chimera effectively induced ubiquitin-mediated degradation of SLC7A11. Consequently, this inactivated cystine/glutamate antiporter (System Xc − ), depleted GPX4, and amplified oxidative stress in cancer cells. Notably, dSLC7A11 exhibited superior antitumor efficacy over sulfasalazine alone, and achieved an effect of suppressing tumor growth by >65% in vivo. This study presented a SLC7A11-targeting PROTAC that disrupts the cellular antioxidant defense system, thus establishing a novel PROTAC-based approach for potent ferroptosis induction in cancer therapy.
研究领域:
肿瘤学
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分子生物学
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靶向治疗
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氧化还原生物学
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药物设计
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DOI
PubMed
高影响因子
Scientific Reports
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2026
·
IF 4.9
Qin Yong,Xu Shengqian,Ye Hailin,Wang Chaojun,Pan Wenjuan
Hepatocellular carcinoma remains a leading cause of cancer-related mortality worldwide. Although lenvatinib is widely deployed as a frontline systemic therapy for advanced disease, its clinical utility is frequently subverted by primary or adaptive non-responsiveness. Evasion of ferroptosis, an iron-dependent form of regulated cell death driven by lipid peroxidation, has emerged as a key survival mechanism for tumor cells under therapeutic stress. While the RNA-binding protein RBMS1 is known to participate in oncogenic progression and ferroptotic regulation across several malignancies, whether it modulates lenvatinib sensitivity in hepatocellular carcinoma by intersecting with the SLC7A11-dependent antioxidant pathway has not been established. Expression profiles of RBMS1 and SLC7A11 were interrogated in paired clinical tissue samples and public transcriptomic datasets. Stable lentiviral overexpression or short hairpin RNA-mediated knockdown was executed in HepG2 and Huh7 cells to modulate candidate gene abundance. Cellular phenotypes, comprising viability, clonogenicity, migration, invasion, and drug sensitivity, were mapped via cell counting kit-eight, colony formation, wound healing, and transwell migration assays. Ferroptotic kinetics and oxidative shifts were tracked by measuring intracellular reactive oxygen species and lipid peroxidation using fluorescent probes. Finally, a subcutaneous xenograft model was established to validate the synergistic potential of RBMS1 depletion with lenvatinib therapy in vivo. In clinical specimens, SLC7A11 was markedly upregulated and tied to shortened overall survival, while RBMS1 expression exhibited a strong upward trend that correlated robustly with SLC7A11 abundance in broader transcriptomic cohorts. Functionally, overexpressing RBMS1 accelerated malignant behaviors, expanded SLC7A11 protein levels, neutralized reactive oxygen species, and shielded cells from lipid peroxidation, ultimately lowering lenvatinib sensitivity. Conversely, silencing RBMS1 yielded opposite phenotypes, aggravating ferroptotic oxidative damage and amplifying lenvatinib responsiveness. Epistatic rescue experiments demonstrated that SLC7A11 knockdown completely abrogated the anti-ferroptotic defense and drug tolerance conferred by RBMS1 hyperactivation. In vivo animal models corroborated these dynamics, showing that RBMS1 knockdown significantly potentiated the antitumor efficacy of lenvatinib. These findings position RBMS1 as a novel upstream post-transcriptional regulator of SLC7A11-dependent ferroptosis susceptibility and lenvatinib responsiveness in hepatocellular carcinoma. By reinforcing the SLC7A11 antioxidant network, RBMS1 shields malignant cells from drug-induced oxidative catastrophe. Targeting this newly uncovered post-transcriptional axis represents a viable therapeutic strategy to overcome lenvatinib tolerance in advanced disease.
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DOI
高影响因子
FREE RADICAL BIOLOGY AND MEDICINE
·
2025
·
IF 8.2
Wenqi Qian,Xijun Chen,Liuqing Gu,Xiangxiang Lin,Jiawei Chen,Dongchen Xu,Hao Wang,Fucai Long,Qichuan ZhuGe,Peng Zhang,Haoqi Ni
An increasing body of evidence indicates that ferroptosis, characterized by lipid peroxidation (LPO), plays a significant role in the neurophysiological and pathological changes following traumatic brain injury (TBI). Herbacetin (HBT), primarily derived from Sedum plants, is hypothesized to possess strong antioxidant activity due to the presence of five phenolic hydroxyl groups in its structure, which may allow it to counteract ferroptosis after TBI, thereby offering a potential therapeutic approach for TBI treatment. In our study, we employed an erastin and RSL3-induced ferroptosis model using HT22 and PC12 cells. Our findings demonstrated that HBT significantly mitigates erastin-induced cell death by reducing reactive oxygen species (ROS) levels, LPO, and Fe 2+ accumulation. Moreover, HBT protected against changes in mitochondrial membrane potential and mitochondrial superoxide levels induced by erastin and RSL3. We further confirmed HBT’s ability to inhibit ferroptosis in the TBI mouse model. HBT reduced the levels of LPO and iron deposition in the tissue surrounding the injury site after TBI, protected neurons, and decreased microglial activation. Mechanistically, we showed that HBT upregulates hypoxia inducible factor-1α (Hif-1α) expression in both ferroptosis cells and the TBI animal model, which in turn leads to the upregulation of recombinant solute carrier family 7 member 11 (SLC7A11) and glutathione peroxidase 4 (GPX4), thereby reducing ferroptosis. RNA-seq analysis and Hif-1α knockdown experiments in HT22 cells supported this conclusion. In conclusion, our findings provide a potential therapeutic basis for the clinical use of HBT in preventing neuronal ferroptosis following TBI.
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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.
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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.
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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.
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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.
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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.
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高影响因子
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