Antioxidants
·
2026
·Vol. 15
·期 7
·888
·
IF 8.2
Yin Liu,Yan Wang,Xinyu Shi,Ruomei Che,Xiaoli He
Background:Danshen–Gegen is a classic herb pair in traditional Chinese medicine, which has been used to treat cardiovascular and cerebrovascular diseases. Ischemic stroke (IS) is a prevalent cerebrovascular condition; ferroptosis is one of the contributing factors driving the progression of IS. This study aims to determine the underlying mechanism and examine if Danshen–Gegen (DG) extract may prevent cerebral ischemia–reperfusion injury by preventing ferroptosis.Methods:The comprehensive compositional characterization of DG was analyzed by ultra-high-performance liquid chromatography coupled with hybrid quadrupole-orbitrap high-resolution mass spectrometry (UPLC-Q-orbitrap MS). The experiments were conducted in middle cerebral artery occlusion/reperfusion (MCAO/R) rats and oxygen-glucose deprivation/re-oxygenation (OGD/R) cells. The neuroprotective effects of DG on IS were assessed by examining rat survival rates, infarct volume, behavioral scores, and cerebral water content. Then, we tested the accumulation of Fe2+and lipid peroxidation products such as reactive oxygen species (ROS), glutathione (GSH), malondialdehyde (MDA), myeloperoxidase (MPO), and 4-hydroxynonenal (4-HNE) in rats and cells. The expression of nuclear factor erythroid-derived 2-like 2 (Nrf2), Solute Carrier Family 7 Member 11 (-xCT), Glutathione peroxidase 4 (GPX4), Cyclooxygenase-2 (COX-2), Transferrin Receptor 1 (TFR1), and Long-chain-fatty-acid–CoA ligase 4 (ACSL4) was also assessed in vivo and in vitro.Results:UPLC-Q-orbitrap MS analysis was performed to characterize the chemical profile of DG, and a total of 33 chemical constituents were successfully identified. DG significantly alleviated the ischemic damage to brain tissue, reduced infarct volume, and improved neurological dysfunction. The content of Fe2+and lipid peroxidation products was markedly decreased. Furthermore, DG could restore the expression of Nrf2, -xCT, and GPX4 with the inhibition of COX-2, TFR1, and ACSL4, thus achieving a suppressive effect on ferroptosis.Conclusions:The regulatory influence of DG via the Nrf2/System xc-/GPX4 axis may play a crucial role in alleviating ferroptosis and enhancing recovery from cerebral ischemia injury.
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BIOCHEMICAL PHARMACOLOGY
·
2026
·
IF 6.5
Tianyue Guan,Audrey Dela,Yichen Jin,Juqin Song,Tingyan Wang,Yu Zhu,Jingquan Dong,Panpan Zhao
Sepsis-induced acute lung injury (ALI) remains a critical factor contributing to mortality in intensive care units, and effective therapeutic strategies are still lacking. The present research explores the defensive impacts and associated mechanisms of Tubuloside A (TA), an active phenanthrenoid glycoside extracted from Cistanche deserticola, in sepsis-induced ALI. Utilizing both a cecal ligation and puncture (CLP) mouse model and LPS-stimulated MLE-12 alveolar epithelial cells, we found that TA markedly attenuated lung injury, as indicated by improved histopathological features, reduced pulmonary edema, and maintenance of alveolar structure. Mechanistically, TA provided multifaceted protection by concurrently inhibiting oxidative stress, ferroptosis, and inflammatory signaling—critical drivers of sepsis-induced ALI. Treatment with TA diminished lipid peroxidation, restored GPX4 expression, and inhibited pro-inflammatory cytokines (TNF-α, IL-6, IL-1β). Network pharmacology identified NFKB1 as a therapeutic target of TA against ALI. Molecular docking predicted and SPR analysis verified that TA binds to NF-κB p50. Notably, functional validation via NF-κB p50 overexpression abolished TA-mediated protection and re-sensitized cells to ferroptosis, confirming NF-κB p50 as a central regulatory node. Furthermore, TA activated Nrf2 signaling in an NF-κBp50–dependent manner, as demonstrated by nuclear translocation assays and rescue experiments. Calcein AM imaging and iron chelation studies confirmed that TA’s anti-ferroptotic effect requires functional NF-κB/Nrf2/GPX4 crosstalk. Collectively, our findings reveal that TA ameliorates sepsis-ALI by targeting the NF-κBp50–Nrf2/GPX4 axis to coordinately inhibit inflammation, oxidative stress, and ferroptosis, highlighting its potential as a multi-target phytotherapeutic agent for acute respiratory disorders
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PHYTOMEDICINE
·
2026
·
IF 11.3
Li Zhen,Jianhong Peng,Huimin Cui,Junhong Tao,Yaping Liu,Jianxin Cao,Hesham R El-Seedi,Guiguang Cheng,Zhengxuan Wang
Background The flowers of Rosa chinensis cv. ‘JinBian’ (RCF) has been utilized as a herbal tea for millennia to prevent aging-related diseases. RCF is enriched in flavonoids and exhibits significant antioxidant effects for anti-aging potential. However, the specific bioactive compounds and their underlying anti-aging mechanisms remain unclear. Purpose This study aimed to investigate the bioactive ingredients and neuroprotective mechanisms of RCF extracts. Methods The study obtained dichloromethane (RD), ethyl acetate (RE), n-butanol (RB), and residual water (RW) fractions from RCF after liquid-liquid extraction. It investigated their neuroprotective effect in in vitro and in vivo experiments. UHPLC-ESI-HRMS/MS analysis was used to identify phytochemicals in RE. In vitro assays included measuring phenolic and flavonoid contents, ABTS⁺ and DPPH + scavenging capacities, and effects on H₂O₂-induced SHSY-5Y cells. In vivo , D-galactose-induced mice were used and assessed through the Morris water maze test and the crucifixion anxiety test. Molecular pathways and gut microbiota were analyzed. Results Among the fractions, RE had the highest phenolic and flavonoid contents, the strongest ABTS⁺ and DPPH + scavenging capacities, and significantly inhibited ROS accumulation by increasing antioxidants (glutathione, catalase, superoxide dismutase) in H₂O₂-induced SHSY-5Y cells. UHPLC-ESI-HRMS/MS analysis identified 28 phytochemicals in RE, primarily gallic acid derivatives and flavonoid derivatives. In D-galactose-induced mice, RE alleviated memory impairment and anxiety-like behavior. RE ameliorated brain damage by activating the Keap1/Nrf2-regulated antioxidant pathway (increasing T-AOC, GSH, GPX4, NQO1, SOD1, HO-1), suppressing ferroptosis, inhibiting acetylcholinesterase activity, attenuating GSK-3β/Tau/Bcl-2 axis-regulated apoptosis, and modulating AMPK-regulated autophagy. Additionally, RE improved gut microbiota diversity, particularly increasing beneficial bacteria such as Lactobacillus and Bifidobacterium . Conclusions Therefore, RE could alleviate the cognitive deficit associated with age-related neurodegenerative diseases by targeting ferroptosis-related oxidative stress, apoptosis, and autophagy, as well as modulating the gut microbiota.
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Nature Communications
·
2024
·Vol. 15
·期 1
·1-17
·
IF 14.7
Wang Huirui,You Xiaona,Wang Jingcheng,Chen Xinyi,Gao Yinghui,Wang Mengmeng,Zhang Wenru,Zhang Jiaozhen,Yu Yang,Han Bo,Qi Mei,Liu Xiaohui,Lou Hongxiang,Dong Ting
Hemolysis drives susceptibility to lung injury and predicts poor outcomes in diseases, such as malaria and sickle cell disease (SCD). However, the underlying pathological mechanism remains elusive. Here, we report that major facilitator superfamily domain containing 7 C (MFSD7C) protects the lung from hemolytic-induced damage by preventing ferroptosis. Mechanistically, MFSD7C deficiency in HuLEC-5A cells leads to mitochondrial dysfunction, lipid remodeling and dysregulation of ACSL4 and GPX4, thereby enhancing lipid peroxidation and promoting ferroptosis. Furthermore, systemic administration of MFSD7C mRNA-loaded nanoparticles effectively prevents lung injury in hemolytic mice, such as HbSS-Townes mice and PHZ-challenged 7 C −/− mice. These findings present the detailed link between hemolytic complications and ferroptosis, providing potential therapeutic targets for patients with hemolytic disorders.
研究领域:
分子生物学
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细胞生物学
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药理学
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病理学
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COLLOIDS AND SURFACES B-BIOINTERFACES
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2024
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IF 5.4
Xinyu Zhao,Huirong Huang,Xinyu Jiang,Shimin Zheng,Chenyu Qiu,Yingfeng Cheng,Yinhao Lin,Yunzhi Wang,Yuqi Yan,Xinyu Di,Miyun Hu,Wanling Zhu,Fugen Wu,Xianbao Shi,Ruijie Chen,Longfa Kou
Osteoarthritis (OA) is a chronic inflammation that gradually leads to cartilage degradation. Prolonged chondrocyte oxidative stress contributes to the development of diseases, including chondrocyte apoptosis, cartilage matrix degradation, and aggravation of articular cartilage damage. Bilirubin (BR) possesses strong antioxidant properties by scavenging reactive oxygen species (ROS) and potent protection effects against inflammation. However, its insolubility and short half-life limit its clinical use. Therefore, we developed a supramolecular system of ε-polylysine (EPL) conjugated by β-cyclodextrin (β-CD) on the side chain, and bilirubin was loaded via host-guest interactions, which resulted in the self-assemble of this system into bilirubin-loaded polylysine-β-cyclodextrin nanoparticle (PB) with improving solubility while reducing toxicity and prolonging medication action time. To explore PB's potential pharmacological mechanisms on OA, we established in vitro and in vivo OA models. PB exerted ROS-scavenging proficiency and anti-apoptotic effects on rat chondrocytes by activating the Nrf2-HO-1/GPX4 signaling pathway. Additionally, PB reprogrammed the cartilage microenvironment by regulating the NF-κB signaling pathway to maintain chondrocyte function. Animal experiments further confirmed that PB had excellent scavenging ability for ROS and inflammatory factors related to charge adsorption with cartilage as well as long retention ability. Together, this work suggests that PB has superior protective abilities with beneficial effects on OA, indicating its great potential for intervention therapy targeting chondrocytes.
研究领域:
药理学
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纳米技术
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骨科
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炎症
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氧化应激
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JOURNAL OF NANOBIOTECHNOLOGY
·
2026
·Vol. 24
·期 1
·914
·
IF 15
Li Chenhao,Zhang Chao,Zhang Chuanqi,Duan Shiyu,Zhang Jiali,Wang Hongyue
AKI-to-CKD progression is shaped by sustained tubular stress, ferroptosis-related iron imbalance, and oxidative injury. To target this process, we developed an MHY1485-loaded molybdenum oxide (MoOx) nanozyme coated with a pH-responsive phenylboronic acid-polyethylene glycol-phenylboronic acid (PBA-PEG-PBA) polymer (MHY@MO@PPP). We tested whether this platform could weaken the ferroptosis-associated injury loop and delay AKI-to-CKD transition through regulation of the Fe 2+ -mechanistic target of rapamycin complex 1 (mTORC1)-glutathione peroxidase 4 (GPX4) axis. Material properties were examined by dynamic light scattering (DLS), transmission electron microscopy (TEM), X-ray photoelectron spectroscopy (XPS), and liquid chromatography-tandem mass spectrometry (LC-MS/MS). Biological activity was assessed in erastin-induced ferroptotic human renal proximal tubular epithelial (HK-2) cells and in a C57BL/6 mouse unilateral ischemia-reperfusion injury (UIRI) model. MHY@MO@PPP showed stimulus-responsive MHY1485 release under simulated lesion-like conditions, lowered reactive oxygen species (ROS), lipid peroxidation, and free Fe 2+ , restored mitochondrial function, and improved cell survival. Mechanistic assays showed increased p-mTOR and GPX4 expression with reduced autophagy-related stress, supporting attenuation of the ferroptosis-related feedback state. Proteomic analysis and functional intervention experiments further implicated the Fe 2+ -mTORC1-GPX4 axis in the protective response. In vivo, MHY@MO@PPP improved renal function and reduced renal tissue injury and fibrosis. These findings support a nanozyme-based strategy that combines catalytic redox regulation with pathway modulation to mitigate AKI-to-CKD progression. Graphical abstract
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INTERNATIONAL IMMUNOPHARMACOLOGY
·
2024
·
IF 4.8
Chenlu Huo,Shuang Li,Anting Liu,Yujie Hong,Yan Zhu
It has been reported that the symptoms of rheumatoid arthritis (RA) can be ameliorated by acupuncture, an external treatment of traditional Chinese medicine. However, the immune mechanism underlying its action is elusive. Accordingly, this study investigated the role and mechanism of manual acupuncture (MA) in collagen-induced arthritis (CIA) in mice. The results demonstrated that MA or NaB treatment reduced Articular Index scores and right paw thickness and alleviated synovial inflammation and cartilage damage. MA or NaB treatment altered the content and relative abundance of short-chain fatty acids, particularly butyric and propionic acids, in feces. Additionally, MA or NaB treatment elevated SCD1, SREBP1, and GPX4 protein expression in synovial tissues and GSH-px contents in serum while decreasing ROS fluorescence intensity and MDA contents in peripheral blood. A linear correlation was found between the relative expression of SCD1 and SREBP1 in synovial tissues and the contents of propionic acids and butyric acids in feces, as well as between the contents of propionic acids and butyric acids. In summary, MA regulates butyric acids to inhibit ferroptosis, therefore suppressing inflammation in RA.
研究领域:
免疫学
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风湿病学
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中医
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分子生物学
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ADVANCED FUNCTIONAL MATERIALS
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2025
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IF 19
Xinghua Yu,Yujun Zhang,Lingan Zeng,Haiyan Chen,Xuemei Dong,Tianfu Zhang,Ben Zhong Tang,Fei Sun
Asthenozoospermia, a major cause of male infertility characterized by impaired sperm motility, is critically driven by oxidative stress and dysregulated iron metabolism, which directly induce ferroptosis in sperm cells. To address this, a novel nanotheranostic platform utilizing ferritin nanocages to encapsulate vitexin, a natural flavonoid with potent antioxidant properties and unique aggregation-induced emission (AIE) characteristics, is introduced. This ferritin nanocage-loaded vitexin (HFn@VI) system combines the iron-chelating capability of ferritin with vitexin's ability to mitigate oxidative stress, enabling precise dual-targeting of the ferroptotic pathways in spermatogenic cells. In the asthenozoospermia model mice, HFn@VI significantly improves sperm count and kinematic parameters (motility, velocity) without observable systemic toxicity, demonstrating superior therapeutic efficacy. Mechanistic studies reveal that the ferritin component elevates ferritin heavy chain 1(FTH1) levels, sequestering free iron ions and reducing cellular iron overload. Concurrently, vitexin activates the nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) pathway, enhancing glutathione peroxidase 4 (GPX4) expression to inhibit lipid peroxidation and ferroptosis. This study pioneers the application of vitexin, a natural product exhibiting AIE characteristics, as a therapeutic agent in reproductive medicine and underscores the potential of dual-target nanomedicines for precise ferroptosis intervention, establishing a new paradigm for treating male infertility through advances in material science.
研究领域:
纳米医学
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生殖医学
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泌尿科学
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分子生物学
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材料科学
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International Heart Journal
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2024
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IF 1.2
Xiaoyu Shen,Jiamei Zhang,Zhou Zhou,Ruiqun Yu
Cardiomyocyte lipotoxicity and ferroptosis are the key to the development of diabetic cardiomyopathy (DCM). Perilipin 5 (PLIN5) is perceived as a significant target of DCM. This study aimed to focus on the role and mechanism of PLIN5 on lipotoxicity and ferroptosis in DCM.Following transfection, mouse cardiomyocytes HL-1 were induced by 0.1 mM palmitic acid (PA) to set up lipotoxic cardiomyocyte models. The cell viability and lipid accumulation were evaluated by cell counting kit-8 assay and Oil red O staining, respectively. Ferrous ion (Fe2+), glutathione (GSH), malondialdehyde (MDA), and reactive oxygen species (ROS) levels were determined to verify the effects of PLIN5 or Pirin (PIR) on ferroptosis. Quantitative real-time reverse transcription polymerase chain reaction or Western blot was performed for quantitative analysis.PLIN5 overexpression promoted the viability, GSH level, and expression of GPX4/PIR/intracellular P65, yet suppressed lipid accumulation, level of Fe2+/MDA/ROS, and expression of interleukin (IL) -1β/IL-18/intranuclear P65 in PA-stimulated HL-1 cells. PIR silencing counteracted the roles of PLIN5 overexpression in PA-stimulated HL-1 cells.PLIN5 suppresses lipotoxicity and ferroptosis in cardiomyocyte via modulating PIR/NF-κB axis, hinting its potential as a therapeutic target in DCM.
研究领域:
心脏病学
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细胞生物学
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分子生物学
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糖尿病
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病理学
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高影响因子
Acta Pharmaceutica Sinica B
·
2024
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IF 14.7
Danni Liu,Yaoqi Wang,Qi Sun,Dong Mei,Xiaoling Wang,Yan Su,Jie Zhang,Ran Huo,Yang Tian,Siyu Liu,Shuang Zhang,Chunying Cui
Ferroptosis has received great attention as an iron-dependent programmed cell death for efficient cancer therapy. However, with the accumulation of iron in tumor cells, the antioxidant system is activated by reducing glutathione (GSH) with glutathione peroxidase 4 (GPX4), which critically limits the ferroptosis therapeutic effect. Herein, an iron and GPX4 silencing siRNA (siGPX4) co-encapsulated ferritin nanocage (HFn@Fe/siGPX4) was developed to enhance ferroptosis by disruption of redox homeostasis and inhibition of antioxidant enzyme synergistically. The siGPX4 were loaded into the nanocages by pre-incubated with iron, which could significantly improve the loading efficiency of the gene drugs when compared with the reported gene drug loading strategy by ferritin nanocages. And more iron was overloaded into the ferritin through the diffusion method. When HFn@Fe/siGPX4 was taken up by human breast cancer cell MCF-7 in a TfR1-mediated pathway, the excess iron ions in the drug delivery system could for one thing induce ferroptosis by the production of reactive oxygen species (ROS), for another promote siGPX4 escaping from the lysosome to exert gene silencing effect more effectively. Both the in vitro and in vivo results demonstrated that HFn@Fe/siGPX4 could significantly inhibit tumor growth by synergistical ferroptosis. Thus, the developed HFn@Fe/siGPX4 afforded a combined ferroptosis strategy for ferroptosis-based antitumor as well as a novel and efficient gene drug delivery system.
研究领域:
癌症治疗
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纳米技术
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基因递送
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细胞生物学
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肿瘤学
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ACS Nano
·
2018
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IF 13.709
Shuaifei Wang,Fangyuan Li,Ruirui Qiao,Xi Hu,Hongwei Liao,Lumin Chen,Jiahe Wu,Haibin Wu,Meng Zhao,Jianan Liu,Rui Chen,Xibo Ma,Dokyoon Kim,Jihong Sun,Thomas P. Davis,Chunying Chen,Jie Tian,Taeghwan Hyeon,Daishun Ling
Ferroptosis, an iron-based cell-death pathway, has recently attracted great attention owing to its effectiveness in killing cancer cells. Previous investigations focused on the development of iron-based nanomaterials to induce ferroptosis in cancer cells by the up-regulation of reactive oxygen species (ROS) generated by the well-known Fenton reaction. Herein, we report a ferroptosis-inducing agent based on arginine-rich manganese silicate nanobubbles (AMSNs) that possess highly efficient glutathione (GSH) depletion ability and thereby induce ferroptosis by the inactivation of glutathione-dependent peroxidases 4 (GPX4). The AMSNs were synthesized via a one-pot reaction with arginine (Arg) as the surface ligand for tumor homing. Subsequently, a significant tumor suppression effect can be achieved by GSH depletion-induced ferroptosis. Moreover, the degradation of AMSNs during the GSH depletion contributed to T1-weighted magnetic resonance imaging (MRI) enhancement as well as on-demand chemotherapeutic drug release for synergistic cancer therapy. We anticipate that the GSH-depletion-induced ferroptosis strategy by using manganese-based nanomaterials would provide insights in designing nanomedicines for tumor-targeted theranostics.
研究领域:
纳米技术
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癌症研究
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诊疗学
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材料科学
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高影响因子
Bioactive Materials
·
2024
·
IF 18
Yulu Yang,Xianhui Zhang,Yao Yang,Pengfei Gao,Wuzhe Fan,Tao Zheng,Weihu Yang,Yu Tang,Kaiyong Cai
Postmenopausal osteoporosis (PMOP) is a prevalent condition among elderly women. After menopause, women exhibit decreased iron excretion, which is prone to osteoporosis. To design a specific titanium implant for PMOP, we first analyze miRNAs and DNA characteristics of postmenopausal patients with and without osteoporosis. The results indicate that iron overload disrupts iron homeostasis in the pathogenesis of PMOP. Further experiments confirm that iron overload can cause lipid peroxidation and ferroptosis of MSCs, thus breaking bone homeostasis. Based on the findings above, we have designed a novel Ti implant coated with nanospheres of caffeic acid (CA) and deferoxamine (DFO). CA can bind on the Ti surface through the two adjacent phenolic hydroxyls and polymerize into polycaffeic acid (PCA) dimer, as well as the PCA nanospheres with the repetitive 1,4-benzodioxan units. DFO was grafted with PCA through borate ester bonds. The experimental results showed that modified Ti can inhibit the ferroptosis of MSCs in the pathological environment of PMOP and promote osseointegration in two main ways. Firstly, DFO was released under high oxidative stress, chelating with excess iron and decreasing the labile iron pool in MSCs. Meanwhile, CA and DFO activated the KEAP1/NRF2/HMOX1 pathway in MSCs and reduced the level of intracellular lipid peroxidation. So, the ferroptosis of MSCs is inhibited by promoting the SLC7A11/GSH/GPX4 pathway. Furthermore, the remained CA coating on the Ti surface could reduce the extracellular oxidative stress and glutathione level. This study offers a novel inspiration for the specific design of Ti implants in the treatment of PMOP.
研究领域:
生物材料
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骨科
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材料科学
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细胞生物学
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生物医学工程
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