Cell Death Discovery
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2025
·Vol. 11
·期 1
·1-16
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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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产品关联
DOI
PubMed
高影响因子
COLLOIDS AND SURFACES A-PHYSICOCHEMICAL AND ENGINEERING ASPECTS
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2025
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IF 5.4
Junling An,Hao Li,Wenjing Wen,Gaojian Liu,Zixuan Huang,Xinwei Zhao,Gaofeng Liang
Liver cancer, particularly hepatocellular carcinoma (HCC), presents significant therapeutic challenges due to factors such as drug resistance and systemic toxicity. Ferroptosis, an iron-dependent form of cell death, offers a promising alternative to overcome these challenges. This study investigates the use of folic acid-modified iron oxide nanoparticles as a delivery system for miR-214-3p to promote ferroptosis in liver cancer cells. The folic acid modification enhances the efficiency of nanoparticle-mediated miR-214-3p delivery, thereby improving its therapeutic potential. miR-214-3p plays a dual role in promoting ferroptosis: first, by downregulating lipocalin-2 (LCN2), it acts synergistically with iron oxide nanoparticles to increase intracellular iron levels, reduce iron excretion, and promotes the Fenton reaction; second, by inhibiting glutathione peroxidase 4 (GPX4), it weakens cellular antioxidant defenses, further promoting ferroptosis. Our in vitro experiments demonstrated that the folic acid-modified nanoparticles effectively delivered miR-214-3p, resulting in significant ferroptosis in liver cancer cells. Animal models showed that FeNP/miR could effectively target tumors and had excellent tumor suppressive effects. This research highlights a promising approach for targeting HCC through enhanced nanoparticle-based gene therapy, offering a potential strategy in cancer treatment.
研究领域:
肿瘤学
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分子生物学
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纳米医学
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产品关联
DOI
高影响因子
RENAL FAILURE
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2025
·
IF 3
Ningjun Shao,Kedan Cai,Yue Hong,Lingping Wu,Qun Luo
Nuclear factor erythroid 2-related factor 2 (Nrf2) regulates many critical genes associated with iron storage and transportation, the activity of which is influenced by E3 ligase-mediated ubiquitination. We wondered whether there is a deubiquitinase that mediates the deubiquitination of Nrf2 to stabilize Nrf2 expression and further prevent diabetic kidney disease (DKD). High glucose (HG) was applied to induce an in vitro model of DKD. The effects of HG on HK-2 cell viability, apoptosis, Fe2+ level, Nrf2, and ubiquitin-specific protease 9X (USP9X) were assessed by cell counting kit-8 (CCK-8) assay, flow cytometry, iron assay, and Western blot. The direct interaction between Nrf2 and USP9X was analyzed using co-immunoprecipitation and ubiquitination assay. After transfection and ferrostatin-1 (Fer-1) intervention, Nrf2 and USP9X levels, cell viability, apoptosis, and Fe2+ level were tested again. Reactive oxygen species (ROS), malondialdehyde (MDA), glutathione (GSH) contents, and ferroptosis-related markers were assessed by ROS assay kit, ELISA, and Western blot. HG reduced cell viability and levels of USP9X and Nrf2, while elevating apoptosis and Fe2+ level. An interaction between USP9X and Nrf2 has been verified and USP9X deubiquitinated Nrf2. Nrf2 up-regulation augmented the viability, GSH content, and ferroptosis-related protein expressions, while suppressing the apoptosis, Fe2+ level, MDA, and ROS content in HG-mediated HK-2 cells, which was reversed by USP9X silencing. Fer-1 offset the combined modulation of Nrf2 and siUSP9X on HG-induced HK-2 cells. USP9X mediates Nrf2 deubiquitinase to hamper the ferroptosis in DKD in vitro.
研究领域:
分子生物学
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肾脏病学
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产品关联
DOI
PubMed
高影响因子
BIOCHEMICAL PHARMACOLOGY
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2025
·
IF 5.6
Jiani Zhan,Yijia Chen,Yuying Liu,Yunqiu Chen,Zhiyao Li,Xuewen Li,Zhenning He,Fangzhou Meng,Xiaoyang Qian,Lili Yang,Qing Yang
Ferroptosis is a type of cell death marked by iron-dependent lipid peroxide accumulation. Indoleamine 2,3-dioxygenase 1 (IDO1), a key enzyme in the catabolism of tryptophan through kynurenine pathway, participates in the development of multiple tumor types. However, the role of IDO1 in tumor ferroptosis is unclear. In this study, we identified IDO1 as a key regulator of ferroptosis in lung cancer. With Erastin-treated lung cancer cells, we found that IDO1 inhibited ferroptosis, reduced the generation of lipid peroxide and ROS. Mechanistically, IDO1 promoted the expression of nuclear factor erythroid 2-related factor 2 (NRF2) through activating aryl hydrocarbon receptor (AhR) pathway. IDO1 up-regulated the expression of solute carrier family 7 member 11 (SLC7A11) and the activity of pentose phosphate pathway (PPP) via AhR-NRF2 axis, promoted the production of reduced nicotinamide adenine dinucleotide phosphate (NADPH) and glutathione (GSH), thereby inhibiting ferroptosis. Moreover, combined treatment with IDO1 inhibitor and Erastin inhibited tumor growth, down-regulated SLC7A11 expression and PPP activity, promoted tumor ferroptosis in lung cancer-bearing mice. In conclusion, this study revealed the function of IDO1 in lung cancer ferroptosis and provided a new strategy for lung cancer therapy.
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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产品关联
DOI
PubMed
高影响因子
ACS Nano
·
2024
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IF 15.8
Qiuyu Li,Zede Wu,Siwen Chen,Yu Liang,Kai Zhu,Ning Su,Tiancai Liu,Bingxia Zhao
Ferroptosis plays an important role in radiotherapy (RT), and the induction of ferroptosis can effectively sensitize radiotherapy. However, the therapeutic efficiency is always affected by ferroptosis resistance, especially SLC7A11 (Solute Carrier Family 7 Member 11)-cystine-cysteine-GSH (glutathione)-GPX4 (glutathione peroxidase 4) pathway-mediated resistance. In this study, tumor-microenvironment self-activated high-Z element-containing nanoferroptosis inducers, PEGylated Fe–Bi–SS metal–organic frameworks (FBSP MOFs), were developed to sensitize RT. Unexpectedly, ferroptosis-resistant SLC7A11 would be self-adaptively upregulated, leading to self-responsive ferroptosis resistance. Since the conversion from SLC7A11-transported cystine to cysteine is highly glucose-dependent, glucose oxidase (GOx) was incorporated in the MOFs, causing the depletion of NADPH (nicotinamide adenine dinucleotide phosphate) to terminate the conversion from cystine to cysteine, relieving the self-adaptive ferroptosis resistance. Excitingly, the accumulation of cystine would synergistically lead to disulfide stress and trigger disulfidptosis, making a new contribution to enhance therapeutic efficiency. Moreover, the hydrogen peroxide produced during glucose oxidation could also cascade-react with the Fenton reaction, therefore enhancing ferropotosis. Both in vitro and in vivo results suggested that therapeutic efficiency of ferroptosis-mediated radiosensitization could be enhanced benefiting from synergistic disulfidptosis induction, indicating that disulfidptosis might be an efficient strategy to relieve ferroptosis resistance and enhance RT efficiency.
研究领域:
肿瘤学
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放射生物学
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纳米医学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
Chemical & Biomedical Imaging
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2024
·
IF 0
Xing Tian,Jiayi Cheng,Lei Yang,Zhanxian Li,Mingming Yu
Hydrogen peroxide and polarity are closely related to many physiological activities and pathological processes. However, near-infrared fluorescent probes that are sensitive to both H2O2 and polarity are still scarce. Herein, we developed the first dual-channel near-infrared fluorescent probe NBO, with an AIE effect, enabling simultaneous monitoring of H2O2 and polarity. The probe presented high sensitivity, high selectivity, and low detection limit for H2O2. It also had high sensitivity to polarity, independent of pH and viscosity, with large Stokes shifts, good photostability, and low cytotoxicity. Moreover, NBO was able to detect both endogenous and exogenous H2O2 as well as polarity fluctuations in vivo as a method to effectively differentiate between cancer cells and normal cells. Importantly, it also could monitor the therapeutic effects of drugs in inflammation and iron-dead cells and mice. Based on NIR emission, NBO could be used as an imaging tool and a way to evaluate the therapeutic effect of drugs for inflammation and ferroptosis.
研究领域:
生物化学
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细胞生物学
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药理学
·
分子成像
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DOI
AMERICAN JOURNAL OF PATHOLOGY
·
2025
·
IF 3.6
Lin Xu,Yuanyuan Zhao,Yang Yang,Enbo Qi,Boao Liu,Peili Zhuang,Shiyi Song,Tingmin Chang,Zhiguo Chen,Xiaohong Kang,Xiwen Xiong
Alcohol-related liver disease (ALD), a consequence of excessive alcohol use, manifests across a broad spectrum of liver damage, ranging from steatosis to cirrhosis. DEPDC5 is a component of the GATOR1 complex, which functions as a repressor of the amino acid-sensing branch of the mTORC1 pathway. In this study, hepatocyte specific Depdc5 knockout mice (Depdc5 △Hep ) were generated and it was found that aberrant activation of mTORC1 caused by Depdc5 deletion led to exacerbated ER stress and hepatocyte ferroptosis in the livers of ethanol-fed mice. Torin-1, an ATP-competitive mTOR inhibitor, suppressed the mTORC1 activity and reversed the effects of Depdc5 deletion on ER stress and ferroptosis in ethanol-fed mouse livers. Furthermore, pharmacological relief of ER stress using TUDCA or inhibition of ferroptosis with liproxstatin-1 both alleviated the liver abnormalities induced by Depdc5 ablation in ethanol-fed mice. Additionally, the research uncovered that ER stress functions as an upstream signal of ferroptosis in the progression of ALD. These findings provide novel in vivo evidence that sustained mTORC1 activation leads to alcoholic liver injury by inducing ER stress and ferroptosis, suggesting that targeting these pathways may represent a potential therapeutic strategy for ALD.
研究领域:
医学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
BIOMATERIALS
·
2025
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IF 12.9
Yuanlin Wang,Yaqian Han,Jingshi Li,Zhaotong Wang,Kai Li,Tiancheng Bai,Lei Wang,Ye Sun,Chunying Chen,Miao Yu
Ferroptosis serves as a pivotal mechanism in diverse clinical chemotherapeutics and physiological processes, profoundly impacting tumor metabolism and the tumor microenvironment. Recently, the immunosuppression induced by ferroptosis has raised major concerns regarding tumor recurrence upon ferroptosis-based antitumor therapies. However, due to the lack of cell specificity, the antitumor and immunosuppressive effects in ferroptosis are inherently intertwined. Herein, we address the conflicting challenges between immunosuppression and antitumor efficacy in ferroptosis-based therapy by enabling cell-specific ferroptosis, thereby targeting tumors while sparing immune cells. By employing a specially designed nanoagent, i.e. , ferrous selenide half-shell-covered gold, we induce notable upregulation of glutathione peroxidase 4 (GPX4) and downregulation of prostaglandin E2, leading to an increase in CD 4+ and CD 8+ T cell populations and intense antitumor immune responses. Despite the elevated level of GPX4, significant tumor cell ferroptosis is achieved, which is further promoted by the agent's photothermal and photocatalytic effects. Consequently, long-term immunological memory is established, yielding a long-lasting and recurrence-free antitumor efficacy spanning at least 200 days post-treatment. This work unlocks an avenue to balance immunosuppression reversal with tumor inhibition in ferroptosis-based therapies, providing promising prospects for antitumor therapies facing immunological hurdles in the tumor microenvironment.
研究领域:
肿瘤学
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免疫学
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纳米医学
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产品关联
DOI
PubMed
高影响因子
COLLOIDS AND SURFACES B-BIOINTERFACES
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2025
·
IF 5.6
Jiashuai Yan,Di Wu,Biwen Zhu,Xiaoqi Guan,Xue Zhang,Yibing Guo,Yuhua Lu
As a highly aggressive solid tumor, pancreatic ductal adenocarcinoma (PDAC) is featured by a conspicuous tumor microenvironment (TME) with abundant extracellular matrix (ECM) deposition, such as collagen and hyaluronic acid (HA). Accompanying with the pathological process, the dense matrix caused stiffen microenvironment, which leads to poor chemotherapy. Therefore, understanding the potential mechanism of mechanical microenvironment on PDAC chemoresistance is of great significance. To this end, 3D printed methacrylated gelatin (GelMA) and hyaluronic acid methacryloyly (HAMA) hydrogel model was fabricated to resemble the mechanical microenvironment of PDAC. The results presented that the PDAC cell lines (MIA-PaCa2 and PANC-1) embedded in the hydrogel were distinctively less sensitive to gemcitabine compared to tissue culture plate (TCP) group. Interestingly, immunofluorescence staining and qRT-PCR assay demonstrated that the NRF2 level was elevated, which further upregulated the downstream effectors, such as SLC7A11 and GPX4. Meanwhile, the GSH concentration and GPX4 activity of hydrogel group were increased, while the lipid peroxidation level was reduced, which indicated that the matrix stiffness microenvironment mediated ferroptosis phenotype. Furthermore, RNA interference experiment elaborated that shNRF2 group showcased significantly enhanced sensitivity to gemcitabine, which demonstrated that the biomimetic microenvironment modulated chemoresistance through ferroptosis. All in all, the 3D printed model may serve as a new platform for illustrating the underlying mechanism of the TME induced chemoresistance, and also proposed a novel therapeutic strategy for PDAC through NRF2 inhibition, which effectively promotes ferroptosis to overcome chemoresistance.
研究领域:
肿瘤学
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细胞生物学
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生物医学工程
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产品关联
DOI
PubMed
高影响因子
Frontiers in Pharmacology
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2025
·
IF 4.8
Yuming Zhai,Jiamei Fu,Jianfei Yang,Yabin Zhou
Background: Myocardial infarction (MI) is characterized by high morbidity. In this study, we aimed to elucidate potential targets of Shengxian Decoction (SXD) against MI.Methods: Pairing of SXD active ingredients and MI targets was conducted using the Chinese Medicine System Pharmacological Database, Gene Expression Omnibus (GEO), and STRING databases. The effects of SXD on MI were validated in vitro. Molecular docking was verified using cellular thermal shift assay (CETSA).Results: A total of 40 active ingredients and 28 MI-related targets were obtained. Cross-analysis on 28 targets and cell death-related genes identified two crucial ferroptosis-related targets, namely, dipeptidyl peptidase 4 (DPP4) and heme oxygenase 1 (HMOX1). In cobalt chloride (CoCl2)-induced hypoxic H9c2 cells, SXD could remarkably improve cell viability and inhibit cell death. Meanwhile, SXD treatment significantly affected the ferroptosis-related markers in hypoxic H9c2 cells. Molecular docking and CETSA results showed that quercetin had good binding activity with DPP4 and HMOX1.Conclusion: Important active ingredient quercetin in SXD could exert anti-ferroptosis protective roles on MI through targeting ferroptosis-related genes (DPP4/HMOX1), thereby contributing to the protective role of SXD on MI.
研究领域:
药理学
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分子生物学
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心血管病学
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产品关联
DOI
PubMed
高影响因子
CELL
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2025
·
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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产品关联
DOI
PubMed
高影响因子
AMERICAN JOURNAL OF CHINESE MEDICINE
·
2025
·
IF 5.5
Mei Luo,Yuelian Wang,Xiaodong Liu,Lin Liu,Li Zhu,Guo Chen,Qing Ye,Chengshi He,Xujue Xiao,Jike Li
Among the spectrum of digestive system cancers, hepatocellular carcinoma (HCC) poses a particularly formidable challenge due to its poor prognosis. Geniposide, an iridoid glucoside extracted from the fruit of Gardenia jasminoides Ellis, exhibits a diverse array of biological activities. The goal of this study is to delineate the specific roles and underlying mechanisms of geniposide on the progression of HCC. Cell viability, apoptosis and migration of Huh7 and HepG2 cells were, respectively, assessed via CCK-8, flow cytometry and trans-well assays. The level of reactive oxygen species (ROS) was assessed with a dihydroethidium (DHE) probe. The measurement of mitochondrial membrane potential (MMP) was conducted using JC-1 staining. Ferroptosis-related markers were evaluated by Western Blot assay. Transcriptome sequencing was performed in HCC cells both treated and untreated with geniposide. In vivo experiments were applied with the subcutaneous xenograft tumor model. In vitro experiments revealed that geniposide exerted a concentration-dependent suppression on cell viability and migration, concurrently eliciting apoptosis in HCC cells. Ferroptosis was identified as the main form of geniposide-induced cell death in HCC. Geniposide promoted the iron ions levels, ROS accumulation, and the expression of ferroptosis markers, which were partially reversed by the addition of deferoxamine (DFO, ferroptosis inhibitor). Intersection analysis was applied between upregulated genes of HCC cells and ferroptosis-related genes. DUOX1 was proven to be involved in geniposide-mediated roles in HCC. In vivo experiments further clarified the suppressive effects of geniposide on tumors. Geniposide treatment increased intracellular iron ions and induced ferroptosis in HCC. Geniposide attenuated tumor progression and oxidative stress via DUOX1-mediated ferroptosis.
研究领域:
生物医学
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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
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