FOOD RESEARCH INTERNATIONAL
·
2026
·
IF 8.8
Yueqin Qiu,Shilong Liu,Xinmiao Liao,Wenjing Wang,Jiaxi Tang,Li Wang,Xuefen Yang,Zongyong Jiang
Geniposide alleviated intestinal barrier dysfunction. • Geniposide increased Prevotella copri abundance to alleviate intestinal injury. • Geniposide inhibited diquat-induced intestinal ferroptosis in vivo and in vitro . • Geniposide regulated TRPV4/GPX4-mediated ferroptosis to alleviated intestinal injury. Early weaning disrupts intestinal antioxidant capacity and barrier integrity in human infants and young animals. Geniposide, an iridoid glycoside, exhibits anti-inflammatory and antioxidant activities. However, the mechanism by which geniposide ameliorates weaning-associated intestinal oxidative injury remains to be elucidated. Therefore, this study aimed to investigate whether and how geniposide attenuates intestinal injury, using diquat (DQ)-challenged weaned piglets, mice, and IPEC-J2 cells as experimental models. The results showed that geniposide supplementation significantly alleviated DQ-induced growth inhibition by increasing ADG and ADFI in the piglets. Additionally, geniposide significantly alleviated DQ-induced intestinal barrier damage, as evidenced by increased gene and protein expression of occludin and claudin-1 and decreased intestinal permeability in the ileum. Moreover, geniposide significantly attenuated DQ-induced oxidative stress, as shown by reduced levels of MDA, ROS, and 4-HNE, along with increased activities of T-AOC, GSH-Px, and T-SOD, as well as upregulated protein abundance of NRF2 and GCLM. Microbiome analysis showed that geniposide significantly increased Prevotella copri abundance in the ileum of DQ-challenged piglets. Prevotella copri supplementation alleviated DQ-induced intestinal injury in mice. Transcriptomic and non-targeted metabolomic analyses revealed that geniposide inhibited the DQ-induced ferroptosis signaling pathway. Additionally, geniposide significantly alleviated the DQ-induced the increases in the levels of MDA and Fe 2+ , and restored expression of the anti-ferroptotic proteins GPX4, SLC7A11, and FTL. Mechanistically, geniposide inhibited DQ-induced intestinal ferroptosis through modulation of the TRPV4/GPX4 pathway and increasing Prevotella copri abundance. Collectively, this study revealed that geniposide alleviated DQ-induced intestinal injury by modulating the TRPV4/GPX4-mediated ferroptosis pathway and increasing Prevotella copri abundance, suggesting its potential as a therapeutic agent against weaning-associated intestinal oxidative damage. Download: Download high-res image (117KB) Download: Download full-size image
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DOI
高影响因子
ChemMedChem
·
2025
·
IF 3.4
Lin Li,Yanyan Wu,Weiwei Wang,Kejing Wang,Lin Chen
Prodrug-based self-assembled nanoassemblies, with carrier-free structures and high drug loading, are garnering attention for chemotherapy. Additionally, the synergistic effects of prodrug nanoassemblies combined with multiple cell death pathways deserve further exploration. Ferroptosis has emerged as a powerful nonapoptotic cell death modality, showing significant potential for tumor inhibition. Therefore, prodrug nanoassemblies combined with ferroptosis inducers may achieve amplified antitumor efficacy. Herein, a GPX4 inhibitor (ML210)-loaded SN38 prodrug nanoparticle system is developed to enhance antitumor efficacy via ferroptotic-chemotherapy synergy. In this system, SN38 is conjugated to 1-octadecanol by a disulfide linkage to construct the self-assembly prodrug. DSPE-PEG 2k is applied to stabilize nanoassemblies. It is proven that ML210 is successfully encapsulated into the SN38 prodrug nanoassemblies by the one-step precipitation method. Both prodrug nanoassemblies exhibit good stability and a GSH-responsive release profile. Furthermore, ML210-loaded nanoassemblies show stronger cytotoxicity, greater proliferation inhibition, and obvious ferroptosis activation. In the CT26 mouse model, ML210-loaded prodrug nanoassemblies demonstrated superior antitumor effects. The strategy—using prodrug as “carriers” for ferroptosis inducers—offers a promising approach for synergistic antitumor therapy. Graphical Redox-responsive SN38-SS-1-octadecanol prodrug was synthesized and used as a “carrier” for ferroptosis activator (ML210). It is proven that ML210 can be successfully encapsulated loaded into the SN38 prodrug nanoassemblies by the one-step precipitation method. Both prodrug nanoassemblies exhibited good stability and a GSH-responsive release profile. The co-assembled system of SN38 prodrug and ML210 can enhance antitumor efficiency by inducing multiple cell death pathway.
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PubMed
高影响因子
Bioactive Materials
·
2024
·
IF 18
Chuanlu Lin,Yiqiang Hu,Ze Lin,Longyu Du,Yixin Hu,Lizhi Ouyang,Xudong Xie,Peng Cheng,Jiewen Liao,Li Lu,Ruiyin Zeng,Ping Xia,Zhiyong Hou,Guohui Liu,Hankun Hu
Ferroptosis plays a crucial role in the progression of diabetic wounds, suggesting potential therapeutic strategies to target ferroptosis. Transient receptor potential ankyrin 1 (TRPA1) is a non-selective calcium channel that acts as a receptor for a variety of physical or chemical stimuli. Cinnamaldehyde (CA) is a specific TRPA1 agonist. In in vitro experiments, we observed that high glucose (HG) treatment induced endothelial cell ferroptosis, impairing cell function. CA successfully inhibited endothelial cell ferroptosis, improving migration, proliferation, and tube formation. Further mechanistic studies showed that CA-activated TRPA1-induced Ca 2+ influx promoted the phosphorylation of calmodulin-dependent protein kinase II (CaMKII) and nuclear factor-E 2-related factor 2 (Nrf2) translocation, which contributed to the elevation of glutathione peroxidase 4 (GPX4), leading to the inhibition of endothelial cell ferroptosis. In addition, CA was incorporated into an MMP-9-responsive injectable duplex hybrid hydrogel (CA@HA-Gel), allowing its efficient sustained release into diabetic wounds in an inflammation-responsive manner. The results showed that CA@HA-Gel inhibited wound endothelial cell ferroptosis and significantly promoted diabetic wound healing. In summary, the results presented in this study emphasize the potential therapeutic application of CA@HA-Gel in the treatment of diseases associated with ferroptosis.
研究领域:
药理学
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生物医学工程
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细胞生物学
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伤口愈合
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DOI
PubMed
高影响因子
Cardiovascular Diabetology
·
2024
·Vol. 23
·期 1
·1-19
·
IF 8.5
Tang Yuan-juan,Zhang Zhen,Yan Tong,Chen Ken,Xu Guo-fan,Xiong Shi-qiang,Wu Dai-qian,Chen Jie,Jose Pedro A.,Zeng Chun-yu,Fu Jin-juan
Background Diabetic cardiomyopathy (DCM) is a serious complication in patients with type 1 diabetes mellitus (T1DM), which still lacks adequate therapy. Irisin, a cleavage peptide off fibronectin type III domain-containing 5, has been shown to preserve cardiac function in cardiac ischemia–reperfusion injury. Whether or not irisin plays a cardioprotective role in DCM is not known. Methods and results T1DM was induced by multiple low-dose intraperitoneal injections of streptozotocin (STZ). Our current study showed that irisin expression/level was lower in the heart and serum of mice with STZ-induced TIDM. Irisin supplementation by intraperitoneal injection improved the impaired cardiac function in mice with DCM, which was ascribed to the inhibition of ferroptosis, because the increased ferroptosis, associated with increased cardiac malondialdehyde (MDA), decreased reduced glutathione (GSH) and protein expressions of solute carrier family 7 member 11 (SLC7A11) and glutathione peroxidase 4 (GPX4), was ameliorated by irisin. In the presence of erastin, a ferroptosis inducer, the irisin-mediated protective effects were blocked. Mechanistically, irisin treatment increased Sirtuin 1 (SIRT1) and decreased p53 K382 acetylation, which decreased p53 protein expression by increasing its degradation, consequently upregulated SLC7A11 and GPX4 expressions. Thus, irisin-mediated reduction in p53 decreases ferroptosis and protects cardiomyocytes against injury due to high glucose. Conclusion This study demonstrated that irisin could improve cardiac function by suppressing ferroptosis in T1DM via the SIRT1-p53-SLC7A11/GPX4 pathway. Irisin may be a therapeutic approach in the management of T1DM-induced cardiomyopathy.
研究领域:
内分泌学
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心脏病学
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分子生物学
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药理学
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DOI
PubMed
高影响因子
PATHOLOGY RESEARCH AND PRACTICE
·
2025
·
IF 3.2
Ting-Ting Yang,Xin-Xin Ma,Xuan Zhang,Zhen-Qing Han,Shuang Zhang,Qi Wang,Hong-Wei Dong,Jia-Ren Liu
β-Ionone (BI) has shown the potent inhibitory malignant progression of multiple tumors including gastric cancer in vitro and in vivo. However, the mechanism by which BI inhibits gastric cancer remains to be clarified, especially in ferroptosis, which is a new form of programmed cell death. The aim of this study was to investigate whether BI could induce ferroptosis in gastric cancer and the underlying mechanisms. The results manifested that BI obviously inhibited cell viability and increased the Fe 2 + level, total reactive oxygen species (ROS) and lipid ROS levels and the malondialdehyde (MDA) concentrations, but reduced the mitochondrial membrane potential (MMP) and the expression of SLC7A11 and GPX4 in MKN45 cells and AGS cells ( P < 0.05 or P < 0.01). Besides, BI also arrested cell cycle and decreased the expression of Cyclin D1 and CDK4 ( P < 0.05 or P < 0.01). Mechanistically, BI reduced the levels of β-catenin and pGSK-3β/GSK-3β in MKN45 cells and AGS cells ( P < 0.05 or P < 0.01). Nevertheless, pretreatment with lithium chloride (LiCl), an inhibitor of GSK-3β, reversed BI-induced ferroptosis and cell cycle arrested in MKN45 cells ( P < 0.05). In addition, BI effectively inhibited the growth of gastric cancer xenografts and downregulated the levels of GPX4, SLC7A11, PCNA, β-catenin and pGSK-3β/GSK-3β ( P < 0.05 or P < 0.01). Collectively, our study reveals that BI inhibits proliferation of gastric cancer cells by induction ferroptosis via the Wnt/β-catenin signaling pathway and provides a novel therapy for gastric cancer.
研究领域:
肿瘤学
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细胞生物学
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药理学
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分子生物学
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DOI
PubMed
高影响因子
Food & Function
·
2021
·Vol. 12
·期 24
·12671-12682
·
IF 5.396
Jing-yi Ren,Bo-wen Yin,Xiang Li,Si-qi Zhu,Jin-liang Deng,Yi-ting Sun,Zhen-ao Zhang,Zi-hao Guo,Huan-ting Pei,Fan Zhang,Rui-qiang Li,Feng-ge Chen,Yu-xia Ma
Objective: This study aimed to elucidate the pharmacological effects of sesamin (Ses) and its mechanism of action towards PM2.5-induced cardiovascular injuries. Method: Forty Sprague Dawley (SD) rats were randomly divided into five groups: a saline control group; a PM2.5 exposure group; and low-, middle-, and high-dose Ses pretreatment groups. The SD rats were pretreated with different concentrations of Ses for 21 days. Afterward, the rats were exposed to ambient PM2.5 by intratracheal instillation every other day for a total of three times. The levels of inflammatory markers, including tumor necrosis factor-alpha (TNF-α), interleukin-1beta (IL-1β), and interleukin-6 (IL-6), and indicators related to oxidative responses, such as total superoxide dismutase (SOD), reduced glutathione (GSH), glutathione peroxidase (GSH-Px), and malondialdehyde (MDA), were measured in the blood and heart. The expression of ferroptosis-related proteins in heart tissues was determined via western blot and immunohistochemistry. Results: Ses pretreatment substantially ameliorated cardiovascular injuries in rats as evidenced by the decrease in the pathological score and collagen area. The decreased levels of SOD, GSH, and GSH-Px in the heart and serum were inhibited by Ses. In addition, Ses not only notably increased the activity of antioxidant enzymes but also reduced the levels of MDA, CK, LDH, CK-MB, IL-6, TNF-α, IL-1β, and IL-6. Furthermore, Ses pretreatment upregulated the expression levels of GPX4, SLC7A11, TFRC, and FPN1 and inhibited the expression levels of FTH1 and FTL. Conclusion: Ses pretreatment could ameliorate PM2.5-induced cardiovascular injuries perhaps by inhibiting ferroptosis. Therefore, Ses pretreatment may be a novel strategy for the prevention and treatment of PM2.5-induced cardiovascular injury.
研究领域:
药理学
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心脏病学
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毒理学
·
环境健康
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DOI
PubMed
高影响因子
CHEMICAL RESEARCH IN TOXICOLOGY
·
2024
·
IF 3.7
Xiuhao Yu,Shaokun Chen,Hailin Wang
Chlorobenzoquinones (CBQs) are a class of emerging water disinfection byproducts that pose significant risks to public health. In this study, we found that three CBQs (tetrachloro-1,4-benzoquinone, 2,5-dichloro-1,4-benzoquinone, and 2-chloro-1,4-benzoquinone) can significantly aggravate cell death caused by Ras-selective lethal small molecule 3 (RSL3). Further study showed that the cell death caused by CBQs, either alone or in combination with RSL3, was related to iron accumulation and GPX4 inactivation, suggesting the occurrence of ferroptosis. Furthermore, reactive oxygen species are found to play a potential key role in mediating the toxicity of CBQs in CBQs and RSL3-induced ferroptosis. These findings will be helpful in understanding the toxic mechanism of CBQs to mammalian cells.
研究领域:
毒理学
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细胞生物学
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环境科学
·
公共卫生
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PubMed
高影响因子
EUROPEAN JOURNAL OF PHARMACOLOGY
·
2021
·
IF 4.432
Chiwei Peng,Xiang Fu,Kaixuan Wang,Ling Chen,Beijiao Luo,Ni Huang,Yunfeng Luo,Wei Chen
Intracerebral hemorrhage (ICH) is a severe stroke subtype with high disability and mortality, and no effective treatment is available. Previous research on intracerebral hemorrhage secondary brain injury drugs mainly targeted at cell apoptosis, inflammation and oxidative stress, but did not achieve good effects. In recent years, ferroptosis has become a focus concern in neurological diseases. Ferroptosis is a new type of programmed cell death caused by iron-dependent accumulation of lipid peroxides, in which glutathione peroxidase 4 (GPX4) is a key protein affecting ferroptosis. In this study, we used the STRING protein database to predict the proteins that may be co-expressed with GPX4, and studied the ability of Dauricine(Dau) to up-regulate the expression of GPX4 against ferroptosis and neuroprotection after intracerebral hemorrhage in normal cells in vitro, glutathione peroxidase 4 (GPX4) knockdown cells and collagenase injection in vivo in mouse models of intracerebral hemorrhage. The results showed that glutathione reductase (GSR) was a possible co-expression protein with GPX4. Dau could up-regulate the expression of glutathione peroxidase 4 (GPX4) in intracerebral hemorrhage(ICH) model, normal cells and GPX4 knockdown cells in vitro, and simultaneously up-regulate the expression of GSR in ICH mice. Dau could also reduce the levels of iron and lipid peroxidation, and have a neuroprotective effect on intracerebral hemorrhage(ICH) mice. It was tesified that Dauricine(Dau) could inhibit ferroptosis of nerve cells and alleviate brain injury after intracerebral hemorrhage by upregulating glutathione peroxidase 4 (GPX4) and glutathione reductase (GSR) co-expression. Therefore, Dau may be an effective drug for inhibiting ferroptosis and treating intracerebral hemorrhage.
研究领域:
神经学
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药理学
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分子生物学
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DOI
PubMed
高影响因子
SENSORS
·
2026
·Vol. 26
·期 3
·836
·
IF 3.5
Yixin Miao,Tao Zhou,Qinghong Ji,Min Hong
Cancer remains a leading global cause of death, with conventional treatments often limited by toxicity and recurrence. Recent advances in gene therapy and nanodrug delivery offer new avenues for precision oncology. Human telomerase reverse transcriptase (hTERT) and glutathione peroxidase 4 (GPX4) are overexpressed in many cancers and linked to apoptosis and ferroptosis, respectively. Here, we developed a manganese dioxide nanosheet (MnO2-NS) probe co-loaded with antisense oligonucleotides targeting hTERT and GPX4 mRNA to synergistically down-regulate both genes and induce dual cell death pathways. The probe, assembled via adsorption of fluorescently labeled antisense strands, showed controllable release in the presence of glutathione (GSH). Cellular uptake and antisense release were confirmed in multiple cancer cell lines. The MnO2-NS probe significantly suppressed cell proliferation, outperforming single-target or carrier-only controls. Molecular analyses confirmed reduced hTERT and GPX4 expression, along with GSH depletion, ROS accumulation, and elevated lipid peroxidation—collectively promoting enhanced cancer cell death. In summary, this MnO2-NS-based co-delivery system enables synergistic gene silencing and GSH depletion, enhancing antitumor efficacy and providing a promising strategy for multifunctional nanotherapy.
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PubMed
高影响因子
APOPTOSIS
·
2026
·Vol. 31
·期 6
·156
·
IF 9
Lv Feng,Li Xiao-huan,Li Si-qi,Deng Hao-wei,Wei Hao-tang,Li Ke-zhi,Xie Ming-zhi,Xie Li-ye,Ning Shu-fang,Hu Bang-li
This study aimed to determine the effect of Artesunate (ART) on oxaliplatin-resistance of colorectal cancer (CRC) and the underlying mechanism. CRC parent and oxaliplatin-resistance cells were induced ferroptosis by ART, overexpression or silence of CDK5 and Nrf2 was conducted on CRC cells, and the function of cells were tested. The protein location, binding effect, protein–protein interaction, ART–CDK5 interaction were determined. Mice model was used to validated the effect of ART on CRC cells. ART induces ferroptosis and inhibits oxaliplatin-resistance of CRC cells. CDK5 promoted the viability, invasive, migration of CRC cells, but did not lead to increases cell apoptosis. CDK5 was associated with ferroptosis and oxaliplatin-resistance of CRC cells, and ART binding and inhibited the expression of CDK5. CDK5 inhibit CRC cells ferroptosis and promote oxaliplatin-resistance; CDK5 binding to Nrf2, increased stability and promote translocation of Nrf2 from cytosol to nuclear. By combination of overexpression of CDK5 and the overexpression or silence of Nrf2 in CRC cells, we found that CDK5 inhibited ferroptosis of CRC cells and enhance resistance to oxaliplatin via Nrf2/GPX4 pathway. The in vivo experiments exhibited that combination of ART and sh-CDK5 reduce the growth of tumors with low toxicity in xenograft models, and reduced Nrf2 and GPX4 expression. ART induced ferroptosis thereby overcomes oxaliplatin-resistance of CRC cells, this effect was via modulating the CDK5/Nrf2/GPX4 pathway. These findings highlight CDK5 as a critical regulator of redox homeostasis in CRC and the therapeutic potential of ART in treating chemoresistant tumors. Graphical abstract The alternative text for this image may have been generated using AI. The present study demonstrate that ART was able to induce ferroptosis via binding and regulation of CDK5, and CDK5 modulates the expression of Nrf2, thereby inhibited biological function of CRC cells and attenuates oxaliplatin-resistance of the cells, this effect was via orchestrating the Nrf2/GPX4 pathway.
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DOI
PubMed
高影响因子
Biomaterials Research
·
2025
·
IF 9.6
Liang Yan,Qi Feng,Yong Sun,Bo-ning Zeng,Chuan-chuan Sun,Qing-bing Zha,Xing-wang Zhang,Shi-ping Zhu
Ferroptosis, a form of lipid peroxidation-mediated cell death, plays a critical role in acute kidney injury (AKI) progression. Tripterine is an active component isolated from traditional medicinal herbs and exhibits diverse biological and pharmacological activities. However, poor bioavailability and cytotoxicity of tripterine has limited its further clinical application, and the underlying action mechanism of tripterine against AKI remains largely unknown. This study aimed to overcome these shortcomings by formulating tripterine into selenized phytosomes and to investigate the therapeutic effects of selenized tripterine phytosomes (Se@Tri-PTs) on ferroptosis-associated AKI. The data showed that Se@Tri-PTs improved the antioxidant capacity of tripterine while reducing its cytotoxicity. Upon erastin or RSL3 stimulation, Se@Tri-PTs maintained intracellular glutathione levels, decreased lipid ROS generation, and suppressed ferroptosis. Mechanistically, Se@Tri-PTs blocked autophagy-mediated degradation of glutathione peroxidase 4 (GPX4), thereby suppressing ferroptosis. Furthermore, Se@Tri-PTs maintained dual-specificity protein phosphatase 1 (DUSP1) protein levels in erastin-stimulated cells, and DUSP1 knockdown reversed Se@Tri-PTs-mediated inhibition of autophagy and ferroptosis. In line with in vitro results, Se@Tri-PTs administration obviously attenuated folic acid-induced AKI and autophagy-dependent ferroptosis in mice. Collectively, these results indicated that Se@Tri-PTs ameliorated ferroptosis and AKI by preserving DUSP1 levels to block autophagy-mediated degradation of GPX4, highlighting their potential in treating ferroptosis-related diseases.
研究领域:
药理学
·
细胞生物学
·
肾脏病学
·
生物化学
·
药物化学
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DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
·
2025
·
IF 8.5
Wang Kai,Wang Renji,Cai Jiarui,Hao Yiguang,Li Ruoyu,Wang Xiaodong,Zhao Yuanting,Yan Liang
Intervertebral disc degeneration (IDD) remains an essential challenge in the clinic. Previous studies have confirmed that persistent inflammation and extracellular matrix (ECM) degradation contribute to the progression of IDD. Inhibiting ferroptotic function is essential for preventing ferroptosis-mediated inflammation and breaking the vicious cycle of ECM degradation. In addition, optimizing the mechanical strength required for physiological maintenance of the ECM is equally important. Herein, this study identifies the potential role of ferroptosis in the pathogenesis of IDD via the bioinformatics analysis, and we thus proposed a novel concept of self-stiffening hydrogel, which enables first to suppress ferroptosis, next to improve inflammatory micro-environment, and finally to optimize mechanical properties to facilitate migration of nucleus pulposus cells. As such, we prepared a self-stiffening hydrogel composed of chitosan/oxidized hyaluronic acid hydrogel (CS/OHA) and curcumin (Cur)-loaded metal-organic frameworks coated by macrophage membrane (Cur-MNPs). The precursor has the potential to decoy inflammatory cytokines as broad-spectrum inflammatory factor inhibitors via coated macrophage membranes. Meanwhile, acidic IDD micro-environment can trigger the specific release of Cur to inhibit ferroptosis-related pathway for alleviating inflammation and restoring the metabolic homeostasis of ECM. Furthermore, the Schiff-base moieties within the hydrogel can scavenge free ferrous ions to mitigate iron overload, converting the unfavorable factors that cause ferroptosis into favorable ligands that optimize mechanical strength. In summary, the novel approach provides a promising paradigm for IDD treatment.
研究领域:
生物医学工程
·
再生医学
·
分子生物学
·
生物材料
·
骨科
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DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）