ADVANCED FUNCTIONAL MATERIALS
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2025
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IF 19
Wenting Xu,Yuzhen Yang,Lijuan Liu,Bangli Hu,Yanping Tang,He Ding,Litu Zhang,Piaoping Yang,Chen Wang
Ferroptosis is a newly identified type of regulated cell death characterized by iron-dependent lipid peroxidation. Among the main ferroptosis-suppressing systems, the dihydroorotate dehydrogenase (DHODH)- ubiquinone axis is closely related to mitochondria and energy metabolism, implying that the axis protects cells from oxidative stress damage via the maintenance of redox homeostasis. However, ferroptosis initiation requires a suitable oxidative environment and a breakthrough in redox homeostatic limitations by ferroptosis-suppressing systems. Hence, the nanoparticles are rationally engineered to achieve efficient ferroptosis induction by releasing dual-release free iron and disrupting ferroptosis-suppressing systems. Atovaquone (ATO)-loaded hollow mesoporous etching zeolitic imidazolate framework-67 double-coated iron oxide/calcium phosphate (Fe 3 O 4 /CaP) is conjugated with polyethylene glycol. The external double-coated Fe 3 O 4 /CaP structure enhances the efficiency of multiple reactive oxygen species (ROS) generation promoting oxidative stress. Still, it achieves free iron dual-release to increase the content of unstable iron pools for igniting the ROS storm and lipid peroxidation spark. The release of ATO not only affects the energy metabolism of the mitochondrial respiratory chain by binding to complex III but also downregulates DHODH to restrict the ubiquinol system to disrupt the ferroptosis-suppressing systems. Therefore, the design of this composite nanomedicine provides an approach for inducing ferroptosis and a theoretical basis for clinical ferroptosis anti-tumor trials.
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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药理学
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DOI
高影响因子
Nature Communications
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2025
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IF 15.7
Fang Zhou,Robert J Ju,Chenlu Kang,Jiayi Li,Ao Yang,Alexandre Libert,Yujie Sun,Ling Liang,Youwei Ai,Xiaoqing Hu,Samantha J Stehbens,Congying Wu
Cells in highly crowded environments are exposed to fluctuating mechanical forces. While cells can activate the cortical migration machinery to escape from undesirable compressive stress, the consequence to less motile cells and of prolonged extensive confinement is yet to be uncovered. Here, we demonstrate that nuclear deformation generated by axial confinement triggers a specific form of regulated cell death – ferroptosis. We show that axial confinement is sensed by the nucleus and results in Drp1-dependent mitochondrial fragmentation and mitochondrial ROS accumulation. Meanwhile, we detect cPLA2 translocation to mitochondria. These mitochondrial ROS accumulation and arachidonic acid production concertedly lead to lipid peroxidation and evoke ferroptosis. Interestingly, we find in osteoarthritis, a disease intimately associated with mechanical overloading and inflammation, characteristics of confinement-induced ferroptosis including mitochondrial localization of cPLA2 and high ROS. Together, our findings unveil a pivotal role of cell nucleus and mitochondria in linking mechanical confinement with cell death, highlighting the orchestration of Drp1 and cPLA2 in confinement-induced ferroptosis. A groundbreaking study reveals how physical confinement triggers ferroptosis. It finds the nucleus acts as a mechanosensor, orchestrating Drp1 and cPLA2 that leads to mitochondrial dysfunction and ultimately, cell death.
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DOI
PubMed
高影响因子
PHYTOTHERAPY RESEARCH
·
2025
·
IF 6.3
Li Li,Wenqian Cai,Hao Zhang,Jiuren Tang,Yongjie Yang,Yang Huang,Qing Xi,Rongxin Zhang
Renal fibrosis is the most common pathway for the development of end-stage renal disease (ESRD) in various kidney diseases. Currently, the treatment options for renal fibrosis are limited. Ferroptosis is iron-mediated lipid peroxidation, triggered mainly by iron deposition and ROS generation. Notably, the kidney is the most sensitive of all tissues to iron-dependent ferroptosis, and the inhibition of ferroptosis is an effective therapeutic strategy for the treatment of kidney fibrosis. Nonetheless, the pathways involved in ferroptosis in renal fibrosis are still unclear. Bergapten, a natural coumarin derivative, is mainly found in bergapten essential oil, grapefruit juice, and other commonly used plants, and it has various pharmacological effects. However, the role that ferroptosis plays in renal fibrosis and the potential therapeutic benefits of bergapten remain unclear. In this study, we investigated the therapeutic effects of bergapten on renal fibrosis and its mechanisms. We investigated the anti-fibrotic effects of bergapten in in vivo and in vitro models of renal fibrosis. Initially, network pharmacological analysis was employed to predict the potential therapeutic impact of bergapten on renal fibrosis. We then explored the potential therapeutic role of bergapten in obstructive nephropathy, which is due to unilateral ureteral obstruction (UUO). Furthermore, RNA-Seq was conducted to investigate the possible mechanism of bergapten against renal fibrosis. Additionally, Bergapten demonstrated a significant improvement in TGF-β1-induced fibrosis and RSL3-induced renal tubular epithelial cell ferroptosis; these findings are consistent with those of the in vivo studies. Our findings indicate that bergapten is a potential treatment for renal fibrosis. Treatment with bergapten significantly reduced the expression of fibronectin and α-SMA in the damaged kidneys of UUO mice, thereby improving fibrosis. Meanwhile, bergapten protected against fibrosis caused by TGF-β1 and ferroptosis induced by glutathione peroxidase 4 (GPX4) inhibitor RSL3. Significantly, bergapten therapy alleviated renal fibrosis by modulating ferroptosis. We found that bergapten inhibited PI3K phosphorylation and indirectly restored GPX4 expression. In conclusion, we have revealed the nephroprotective effect of bergapten, whose mechanism of action is related to the inhibition of ferroptosis, and it is expected that it will be developed as a therapeutic agent for the treatment of renal fibrosis. This study aims to explore the effect of bergapten on renal fibrosis ferroptosis. Collectively, these results demonstrate that bergapten is an inhibitor of ferroptosis and provides a new treatment strategy for diseases associated with ferroptosis.
研究领域:
肾病学
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药理学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
Cell and Bioscience
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2024
·Vol. 14
·期 1
·1-18
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IF 6.1
Maimaiti Yasenjiang,Su Ting,Zhang Zhanying,Ma Lingling,Zhang Yuan,Xu Hong
This study investigates NADPH oxidase 4 (NOX4) involvement in iron-mediated astrocyte cell death in Alzheimer’s Disease (AD) using single-cell sequencing data and transcriptomes. We analyzed AD single-cell RNA sequencing data, identified astrocyte marker genes, and explored biological processes in astrocytes. We integrated AD-related chip data with ferroptosis-related genes, highlighting NOX4. We validated NOX4’s role in ferroptosis and AD in vitro and in vivo. Astrocyte marker genes were enriched in AD, emphasizing their role. NOX4 emerged as a crucial player in astrocytic ferroptosis in AD. Silencing NOX4 mitigated ferroptosis, improved cognition, reduced Aβ and p-Tau levels, and alleviated mitochondrial abnormalities. NOX4 promotes astrocytic ferroptosis, underscoring its significance in AD progression.
研究领域:
神经科学
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分子生物学
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基因组学
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神经退行性疾病
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DOI
PubMed
高影响因子
MICROCHEMICAL JOURNAL
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2024
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IF 4.9
Yan-Ping Liu,Ling-Li Wang,Jing-Yu Piao,Ming-Hua Zheng,Jing-Yi Jin
Ferroptosis is an iron-dependent cell death triggered by lipid peroxidation accumulation, representing a redox imbalance in cells. The increased knowledge of ferroptosis has led to various potential strategies to develop new cancer therapies, such as synergistic ferroptosis-apoptosis. The endoplasmic reticulum (ER) is the major hub for lipid metabolism in cells and plays a central role in lipid peroxidation. Glutathione (GSH) and viscosity levels in ER are important parameters for intracellular redox homeostasis, which remain unclear in ferroptosis and synergistic ferroptosis-apoptosis. This study developed an ER-targeting fluorescent probe (MMPY) with a dual-emission response to GSH and viscosity. Fluorescent cell imaging using MMPY revealed different GSH-viscosity crosstalk in the ER for the four ferroptosis pathways induced by erastin, RSL3, FIN56, and FINO2. GSH and viscosity changes in the ER during synergistic ferroptosis-apoptosis were also investigated. Interestingly, the new types of extracellular vesicles were observed during the synergistic process, which burdened the ER fragments with different GSH contents.
研究领域:
细胞生物学
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生物化学
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医学
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DOI
高影响因子
CELL
·
2026
·
IF 45.1
Wenxiang Huang,Ruijun Wang,Xinquan Yang,Shuangjie Yang,Xueliang Yang,Gaolu He,Songjun Dai,Caizhi Li,Lianchao Gao,Tingting Zhang,Peng Zhang,Ruihan Chen,Keke Zheng,Junbing Wu,Junxia Min,Qian Ba,Fudi Wang,Qiang Zhang
Ferroptosis is an iron-dependent form of regulated cell death. However, the critical regulators that restrain iron overload to suppress ferroptosis remain undefined. Utilizing multi-omics, we identify the E3 ubiquitin ligase membrane-associated RING-CH 7 (MARCH7) as a non-redundant, dual suppressor of ferroptosis via direct regulation of intracellular iron homeostasis. Mechanistically, MARCH7 ubiquitylates nuclear receptor coactivator 4 (NCOA4) at residue Lys42 by K48-linked ubiquitination, promoting NCOA4 proteasomal degradation and reducing the labile iron pool. Concomitantly, MARCH7 modifies transferrin receptor 1 (TFR1) at residue Lys53 by K63 ubiquitination, restricting its plasma membrane translocation and thereby inhibiting cellular iron uptake. Through high-content screening, we further identify emodinanthrone (EmodAn) as a specific MARCH7 stabilizer with a strong cardioprotective effect in rodent models by blocking ferroptosis. In conclusion, our findings define an iron homeostasis regulatory hub for ferroptosis and suggest that stabilizing MARCH7 is a promising therapeutic strategy to protect against ferroptosis- or iron-overload-induced diseases.
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DOI
PubMed
高影响因子
ACS Nano
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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
International Journal of Extreme Manufacturing
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2025
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IF 21.3
Wenxin Xu,Hao Tian,Yanzhen Song,Hanfeng Qin,Junbin Gao,Yichi Chen,Weichang Huang,Lin Lin,Haixin Tan,Yicheng Ye,Xiaoting Zhang,Daniela A Wilson,Guang Yang,Fei Peng,Yingfeng Tu
Ferroptosis is a recently proposed type of programmed cell death, associated with a variety of diseases including tumors. Researchers have thereby presented nanoplatforms to mediate ferroptosis for anti-cancer therapy. However, the development of ferroptosis-based nanotherapeutics was hindered by the limited penetration depth in tumors, poor active pharmaceutical ingredient loading content (API) and the systemic toxicity. Herein, self-propelled ferroptosis nanoinducers composed of two endogenous proteins, glucose oxidase and ferritin, are presented to show enhanced tumor inhibition via ferroptosis while remaining high API and biocompatibility. The accumulation of our proteomotors at tumor regions is facilitated by the active tumor-targeting effect of ferritin. The enhanced diffusion of proteomotors is then actuated by efficiently decomposing glucose into gluconic acid and H2O2, leading to deeper penetration and enhanced uptake into tumors. Under the synergistic effect of glucose oxidase and ferritin, the equilibrium between ROS and GSH was damaged, leading to lipid peroxidation. As a result, by inducing ferroptosis, our self-propelled ferroptosis nanoinducers exhibit enhanced tumor inhibition with negligible systemic toxicity. This work paves a way for constructing a biocompatible cancer treatment paradigm with enhanced diffusion utilizing only two endogenous proteins, centered around the concept of ferroptosis.
研究领域:
纳米技术
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癌症研究
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生物医学工程
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治疗学
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产品关联
DOI
高影响因子
ANALYTICAL AND BIOANALYTICAL CHEMISTRY
·
2024
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IF 3.8
Cong Lili,Shen Yanting,Wang Jiaqi,Meng Fanxiang,Xu Weiqing,Sun Weixia,Xu Shuping
Ferroptosis is a unique form of iron-dependent cell death characterized by dramatic ultrastructural changes in mitochondria. Since mitochondria are intracellular energy factories and binding sites for producing reactive oxygen species, there is increasing evidence that mitochondria are closely related to ferroptosis and play a crucial role in the regulation and execution of ferroptosis. The pH of the mitochondrial microenvironment is an important parameter for cellular physiological activities. Its abnormal fluctuations are commonly thought to be associated with cancers and other diseases. Herein, a surface-enhanced Raman scattering (SERS)–based pH nanosensor with high sensitivity and targeting function was utilized to quantify and monitor mitochondrial pH value. This nanosensor was constructed by gold nanorods (AuNRs) functionalized with pH-responsive molecules (4-mercaptopyridine, MPy) and mitochondrion-targeting peptides (AMMT) that can precisely deliver AuNRs to mitochondria. Super-resolution fluorescence imaging was employed to evidence the mitochondrial targeting feature of this nanosensor. Ferroptosis regulation induces intracellular accumulation of lipid peroxide (LPO) and reactive oxygen species (ROS), which cause changes in the mitochondrial pH. This method reveals that ferroptosis leads to the gradual acidification of the mitochondrial internal environment. The conclusion deduced by this study will be helpful for the evaluation and diagnosis of diseases according to intracellular abnormal microenvironments. Graphical
研究领域:
生物化学
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医学诊断
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细胞生物学
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产品关联
DOI
PubMed
高影响因子
Cell Reports
·
2025
·
IF 6.9
Hui Jiang,Yang Qu,Xianjin Kan,Mengqing Yang,Yabin Gong,Ying Liao,Xusheng Qiu,Lei Tan,Cuiping Song,Venugopal Nair,Chan Ding,Yingjie Sun
Peroxisomes are critical organelles that maintain cellular redox homeostasis. Many viruses induce oxidative stress and degrade peroxisomes, but the mechanisms and consequences remain unclear. In this study, we systematically investigate how virus-induced pexophagy regulates peroxisome homeostasis. Using Newcastle disease virus (NDV) as a model, we demonstrate that NDV infection triggers excessive reactive oxygen species (ROS) production, activating the phosphorylation and peroxisomal localization of ataxia-telangiectasia mutated (ATM). Activated ATM promotes the interaction between the peroxisomal receptor PEX5 and the autophagy receptor p62, driving pexophagy. Pexophagy-mediated peroxisome degradation leads to excess active iron and ROS accumulation, contributing to NDV-induced ferroptosis. Notably, this mechanism is shared by other viruses, such as vesicular stomatitis virus and H9N2 avian influenza virus. Our study provides insights into how virus-induced pexophagy disrupts redox homeostasis to promote ferroptosis, highlighting a link between viral infection, peroxisome degradation, and programmed cell death.
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF CONTROLLED RELEASE
·
2024
·
IF 10.5
Kun Chen,Rui Sun,Yudong Guan,Tao Fang,Jun Tao,Zhijie Li,Bingchen Zhang,Zhiqiang Yu,Jiahang Tian,Zhaogang Teng,Jigang Wang
Ferroptosis-related tumor therapy based on nanomedicines has recently gained significant attention. However, the therapeutic performance is still hindered by the tumor's physical barriers such as the fibrotic tumor matrix and elevated interstitial fluid pressure, as well as chemical barriers like glutathione (GSH) overabundance. These physicochemical barriers impede the bioavailability of nanomedicines and compromise the therapeutic efficacy of lipid reactive oxygen species (ROS). Thus, this study pioneers a manganese-mediated overcoming of physicochemical barriers in the tumor microenvironment using organosilica-based nanomedicine (MMONs), which bolsters the synergy of photothermal-ferroptosis treatment. The MMONs display commendable proficiency in overcoming tumor physical barriers, due to their MnO 2 -mediated shape-morphing and softness-transformation ability, which facilitates augmented cellular internalization, enhanced tumor accumulation, and superior drug penetration. Also, the MMONs possess excellent capability in chemical barrier overcoming, including MnO 2 -mediated dual GSH clearance and enhanced ROS generation, which facilitates ferroptosis and heat shock protein inhibition. Notably, the resulting integration of physical and chemical barrier overcoming leads to amplified photothermal-ferroptosis synergistic tumor therapy both in vitro and in vivo . Accordingly, the comparative proteomic analysis has identified promoted ferroptosis with a transient inhibitory response observed in the mitochondria. This research aims to improve treatment strategies to better fight the complex defenses of tumors.
研究领域:
肿瘤学
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纳米医学
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生物化学
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产品关联
DOI
PubMed
高影响因子
CHEMOSPHERE
·
2020
·
IF 5.778
Zixuan Liu,Xuying Lv,Bingwei Yang,Qi Qin,Erqun Song,Yang Song
Halogenated quinones are representative metabolites of persistent organic pollutants. Tetrachlorobenzoquinone (TCBQ) is a reactive metabolite of the widely used fungicide hexachlorobenzene (HCB) and wood preservative pentachlorophenol (PCP). Our previous studies have demonstrated that TCBQ induced neuron-like cell apoptosis in a reactive oxygen species (ROS)-dependent manner. Here, we found that TCBQ caused lipid peroxidation and cellular morphological changes including shrinked mitochondrial size, suggesting the involvement of a recently uncovered form of programmed cell death (PCD), ferroptosis. Indeed, we then identified that ferroptosis is a novel PCD driven by TCBQ, which was correlated with a decrease in glutathione peroxidase 4 (GPX4) level and iron accumulation by altering iron metabolism. Notably, nuclear factor erythroid-derived 2-like 2 (Nrf2) is a negative regulator in modulating the outcomes of ferroptosis as an adaptive cellular defense response. Nrf2 activation enhanced iron storage capacity and GPX4 activity by elevating ferritin heavy chain 1 (FTH1) expression and glutathione (GSH) level, respectively. On the contrary, Nfe2l2 (Nrf2) deficiency enhanced PC12 cells susceptibility to ferroptosis.
研究领域:
毒理学
·
神经科学
·
细胞生物学
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DOI
PubMed
高影响因子
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