JOURNAL OF MEDICINAL CHEMISTRY
·
2022
·
IF 8.039
Sijin Liu,Xi Zhao,Sufang Shui,Biao Wang,Yingxian Cui,Suwei Dong,Tairan Yuwen,Guoquan Liu
Targeted degradation of proteins, especially those regarded as undruggable or difficult to drug, attracts wide attention to develop novel therapeutic strategies. Glutathione peroxidase 4 (GPX4), the key enzyme regulating ferroptosis, is currently a target with just covalent inhibitors. Here, we developed a targeted photolysis approach and achieved efficient degradation of GPX4. The photodegradation-targeting chimeras (PDTACs) were synthesized by conjugating a clinically approved photosensitizer (verteporfin) to noninhibitory GPX4-targeting peptides. These chimeras selectively degraded the target protein in both cell lysates and living cells upon red-light irradiation. The targeted photolysis of GPX4 resulted in dominant ferroptotic cell death in malignant cancer cells. Moreover, the dying cells resulting from the PDTACs exhibited potent immunogenicity in vitro and efficiently elicited antitumor immunity in vivo. Our approach therefore provides a novel method to induce GPX4 dysfunction based on noncovalent binding and specifically trigger immunogenic ferroptosis, which may boost the application of ferroptosis in cancer immunotherapy.
研究领域:
癌症生物学
·
免疫治疗
·
药理学
·
细胞生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
BIOMEDICINE & PHARMACOTHERAPY
·
2024
·
IF 6.9
Weikang Guo,Wanyue Wang,Fei Lei,Ruxin Zheng,Xinyao Zhao,Yuze Gu,Mengdi Yang,Yunshun Tong,Yaoxian Wang
Cisplatin (DDP) resistance poses a significant challenge in the treatment of ovarian cancer. Studies have shown that the combination of certain polysaccharides derived from plants with DDP is an effective approach to overcoming drug resistance in some cancers. Angelica sinensis (Oliv.) Diels has been used for centuries in China to treat gynecological ailments. Numerous studies indicate that Angelica sinensis polysaccharide (ASP), an extract from Angelica sinensis , can inhibit various forms of cancer. However, the impact of ASP on ovarian cancer remains unexplored. Through both in vitro and in vivo experiments, our study revealed the capability of ASP to effectively reversing DDP resistance in cisplatin-resistant ovarian cancer cells, while exhibiting acceptable safety profiles in vivo. To elucidate the mechanism underlying drug resistance reversal, we employed RNA-seq analysis and identified GPX4 as a key gene. Considering the role of GPX4 in ferroptosis, we conducted additional research to explore the effects of combining ASP with DDP on SKOV3/DDP cells. In summary, our findings demonstrate that the combination of ASP and DDP effectively suppresses GPX4 expression in SKOV3/DDP cells, thereby reversing their resistance to DDP.
研究领域:
肿瘤学
·
药理学
·
分子生物学
·
植物科学
✓ 已验证
DOI
PubMed
高影响因子
ACS Applied Materials & Interfaces
·
2025
·
IF 8.2
Jiayang Luo,Luyao Xu,Jing Feng,Kexin Xu,Peilin Tian,Xianyue Bai,Shihao Xu,Liewei Wen,Cuixia Lu,Jiaxing Song
Photodynamic therapy (PDT) induces apoptosis in cancer cells by generating cytotoxic reactive oxygen species (ROS); however, this effect is constrained by the intrinsic antioxidant mechanisms of the cells and the hypoxic conditions of the tumor microenvironment (TME). To overcome these limitations, a novel ferroptosis-boosted nanophotosensitizer (FCE NPs) is developed after loading alkaloid evodiamine based on an acid-responsive nanoplatform (FC NPs) composed of ferric ions and Chlorin e6 (Ce6). Upon exposure to laser irradiation, the photosensitizer Ce6 efficiently generates singlet oxygen (1O2), which depletes glutathione (GSH), thereby disrupting the redox homeostasis within tumor cells and leading to the oxidation of cellular unsaturated lipid into lipid peroxides (LPO). Additionally, the Fenton reaction between released Fe(III) ions and H2O2 in the TME produces highly cytotoxic hydroxyl radicals (•OH), a form of ROS, causing the accumulation of LPO together with 1O2 to trigger ferroptosis. Following the incorporation of evodiamine, the integrated nanoplatform FCE NPs exhibited excellent antitumor activity through high-performance ferroptosis by inhibiting a glutathione peroxidase 4 (GPX4) level. It was also observed that the key regulator of Wnt signaling pathway β-catenin was downregulated, suggesting the inhibition of FCE NPs on the Wnt signaling pathway. Therefore, this study demonstrated that the FCE NPs could lead to the explosive production of ROS and simultaneous inhibition of GPX4/GSH pathways and the Wnt signaling pathway in colorectal cancer, significantly amplifying the tumoricidal efficacy of PDT through the synergistical sensitization of ferroptosis. This approach offers a promising strategy for the clinical application of ferroptosis therapy.
研究领域:
生物学
·
医学
·
肿瘤学
·
生物化学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Advanced Healthcare Materials
·
2025
·
IF 9.6
Xiaoyu Cui,Bin Chen,Ying Chen,Mi Zhou,Lijun Cao,Bing Hu,Jianrong Wu,Xinxin Ma,Tao Ying
Emerging evidence indicates that modulating glutathione peroxidase 4 (GPX4) to induce ferroptosis is a promising strategy for tumor treatment. However, most of the GPX4 small molecule inhibitors face limitations due to their poor delivery efficacy and low specificity of ferroptosis activation. Herein, a ferroptosis-inducing nanomedicine is developed that integrates nutlin-3 with iridium oxide nanoclusters (NUT-IrO x NCs) for enhanced ferroptosis-driven multimodal therapeutic efficacy in colorectal cancer (CRC). This NUT-IrO x NCs can induce glutathione (GSH) depletion via enhanced Ir (VI)-Ir (III) transition, while nutlin-3, a well-established inhibitor of the p53-MDM2 interaction, suppresses GSH production by modulation of the p53/SLC7A11/xCT signaling pathway. The reduction of intracellular GSH results in pronounced reductions of GPX4 enzymatic activity, consequently leading to lipid peroxidation accumulation and further enhancing ferroptosis-induced CRC therapy. This dual-pronged approach demonstrates robust anticancer therapeutic effects with favorable biocompatibility in both in vitro and in vivo CRC models. This study provides an effective strategy that highlights the benefits of inhibiting of GSH/GPX4 by activating multiple ferroptosis regulatory pathways, providing an alternative therapeutic avenue for CRC treatment.
研究领域:
肿瘤学
·
纳米技术
·
分子生物学
·
癌症治疗
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Redox Biology
·
2024
·
IF 10.7
Yue-Yue Guo,Nan-Nan Liang,Xiao-Yi Zhang,Ya-Hui Ren,Wen-Zheng Wu,Zhi-Bing Liu,Yi-Zhang He,Yi-Hao Zhang,Yi-Chao Huang,Tao Zhang,De-Xiang Xu,Shen Xu
Increasing evidences demonstrate that environmental stressors are important inducers of acute kidney injury (AKI). This study aimed to investigate the impact of exposure to Cd, an environmental stressor, on renal cell ferroptosis. Transcriptomics analyses showed that arachidonic acid (ARA) metabolic pathway was disrupted in Cd-exposed mouse kidneys. Targeted metabolomics showed that renal oxidized ARA metabolites were increased in Cd-exposed mice. Renal 4-HNE, MDA, and ACSL4, were upregulated in Cd-exposed mouse kidneys. Consistent with animal experiments, the in vitro experiments showed that mitochondrial oxidized lipids were elevated in Cd-exposed HK-2 cells. Ultrastructure showed mitochondrial membrane rupture in Cd-exposed mouse kidneys. Mitochondrial cristae were accordingly reduced in Cd-exposed mouse kidneys. Mitochondrial SIRT3, an NAD + -dependent deacetylase that regulates mitochondrial protein stability, was reduced in Cd-exposed mouse kidneys. Subsequently, mitochondrial GPX4 acetylation was elevated and mitochondrial GPX4 protein was reduced in Cd-exposed mouse kidneys. Interestingly, Cd-induced mitochondrial GPX4 acetylation and renal cell ferroptosis were exacerbated in Sirt3 −/− mice. Conversely, Cd-induced mitochondrial oxidized lipids were attenuated in nicotinamide mononucleotide (NMN)-pretreated HK-2 cells. Moreover, Cd-evoked mitochondrial GPX4 acetylation and renal cell ferroptosis were alleviated in NMN-pretreated mouse kidneys. These results suggest that mitochondrial GPX4 acetylation, probably caused by SIRT3 downregulation, is involved in Cd-evoked renal cell ferroptosis.
研究领域:
毒理学
·
肾脏生理学
·
细胞生物化学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
FREE RADICAL BIOLOGY AND MEDICINE
·
2025
·
IF 8.2
Yan Zhang,Yuanyuan Ren,Zhen Wang,Xi Zhang,Xiaofang Li,Yi Yu,Lu Qian,Yuyan Xiong
A high-fat diet and obesity significantly increase the risk of gastric cancer (GC), with persistent obesity contributing to a notable rise in GC incidence. However, the underlying molecular mechanisms remain largely unclear. In this study, we identified exosomal SLC1A5 (Exo-SLC1A5) as a novel senescence-associated secretory phenotype (SASP) factor that promotes GC malignancy. Exosomal SLC1A5 drives GC progression by suppressing ferroptosis in a GPX4-dependent manner. Mechanistically, in the context of obesity, senescent endothelial cells release exosomal SLC1A5, which engages EGFR on GC cells, triggering SRC phosphorylation at Tyr416 and subsequent YAP1 activation at Tyr357. This leads to YAP1 interaction with MYO1B to enhance the nuclear translocation of YAP1, and subsequent upregulation of GPX4, resulting in ferroptosis suppression and accelerated GC progression. In vivo, depletion of exosomal SLC1A5 from PA-induced senescent ECs attenuated GC tumor growth and metastasis in a xenograft mouse model. These findings reveal a novel mechanism by which exosomal SLC1A5 promotes GC progression through the EGFR/SRC/YAP1/GPX4 signaling axis. Targeting the Exo-SLC1A5/EGFR/SRC/YAP1/GPX4 axis may provide a therapeutic strategy for GC.
研究领域:
肿瘤学
·
分子生物学
·
细胞生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
PHYTOTHERAPY RESEARCH
·
2023
·
IF 7.2
Huihui Wang,Baoping Xie,Shuotao Shi,Rong Zhang,Qi Liang,Zhongqiu Liu,Yuanyuan Cheng
Myocardial infarction (MI) is a common disease with high morbidity and mortality. Curdione is a sesquiterpenoid from Radix Curcumae . The current study is aimed to investigate the protective effect and mechanism of curdione on ferroptosis in MI. Isoproterenol (ISO) was used to induce MI injury in mice and H9c2 cells. Curdione was orally given to mice once daily for 7 days. Echocardiography, biochemical kits, and western blotting were performed on the markers of cardiac ferroptosis. Curdione at 50 and 100 mg/kg significantly alleviated ISO-induced myocardial injury. Curdione and ferrostatin-1 significantly attenuated ISO-induced H9c2 cell injury. Curdione effectively suppressed cardiac ferroptosis, evidenced by decreasing malondialdehyde and iron contents, and increasing glutathione (GSH) level, GSH peroxidase 4 (GPX4), and ferritin heavy chain 1 expression. Importantly, drug affinity responsive target stability, molecular docking, and surface plasmon resonance technologies elucidated the direct target Keap1 of curdione. Curdione disrupted the interaction between Keap1 and thioredoxin1 (Trx1) but enhanced the Trx1/GPX4 complex. In addition, curdione-derived protection against ISO-induced myocardial ferroptosis was blocked after overexpression of Keap1, while enhanced after Keap1 silence in H9c2 cells. These findings demonstrate that curdione inhibited ferroptosis in ISO-induced MI via regulating Keap1/Trx1/GPX4 signaling pathway.
研究领域:
药理学
·
心脏病学
·
分子生物学
·
细胞生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
PHARMACEUTICAL BIOLOGY
·
2022
·
IF 3.889
Feng-guo Zhai,Qi-chao Liang,Yi-yan Wu,Jia-qi Liu,Jia-wei Liu
Context Red ginseng polysaccharide (RGP) is an active component of the widely used medicinal plant Panax ginseng C. A. Meyer (Araliaceae), which has displayed promising activities against cancer cells. However, the detailed molecular mechanism of RGP in ferroptosis is still unknown.Objective This study evaluates the effects of RGP in cancer cells.Materials and methods A549 and MDA-MB-231 cells were used. Cell proliferation was measured by CCK-8 assay after being treated with RGP at concentrations of 0, 50, 100, 200, 400, 800 and 1600 μg/mL at 0, 12, 24 and 48 h. Lipid reactive oxygen species (ROS) levels were assessed by C11-BODIPY assay. The control group was treated with PBS.Results RGP inhibited human A549 (IC50: 376.2 μg/mL) or MDA-MB-231(IC50: 311.3 μg/mL) proliferation and induced lactate dehydrogenase (LDH) release, promoted ferroptosis and suppressed the expression of GPX4. Moreover, the effects of RGP were enhanced by the ferroptosis inducer erastin, while abolished by ferroptosis inhibitor ferrostatin-1.Discussion and conclusions Our study is the first to demonstrate (1) the anticancer activity of RGP in human lung cancer and breast cancer. (2) RGP presented the anti-ferroptosis effects in lung and breast cancer cells via targeting GPX4.
研究领域:
肿瘤学
·
药理学
·
细胞生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY
·
2023
·
IF 6.8
Yi He,Fangyang Shi,Jiajun Hu,Hongyu Li,Xun Chen,Lingyu Yuan,Yunyang Lu,Weidong Du,Runze Li,Jie Wu,Feilong Deng,Dongsheng Yu
Magnetic graphene oxide nanocomposites (MGO NPs) have been widely studied in biomedical applications. However, their cytotoxicity and underlying mechanisms remain unclear. In this study, the biosafety of MGO NPs was investigated, and the mechanism involved in ferroptosis was further explored. MGO can produce cytotoxicity in ADSCs, which is dependent on their concentration. Ferroptosis was involved in MGO NP-induced ADSC survival inhibition by increasing total ROS and lipid ROS accumulation as well as regulating the expression levels of ferroptosis-related genes and proteins. GPX4 played a critical role in the MGO NP-induced ADSC ferroptosis process, and overexpressing GPX4 suppressed ferroptosis to increase cell survival. This study provides a theoretical basis for the biosafety management of MGO NPs used in the field of biomedical treatment.
研究领域:
纳米技术
·
生物医学工程
·
细胞生物学
·
毒理学
✓ 已验证
DOI
PubMed
高影响因子
DRUG DEVELOPMENT RESEARCH
·
2025
·Vol. 86
·期 7
·e70174
·
IF 4.2
Zhenfei Yu,Xiaoling Qian,Weihua Wu,Meiqi Zhang,Ying Li
Intracerebral hemorrhage (ICH) is a serious acute cerebrovascular disease with a high death and disability rate. Baicalin plays a neuroprotective role in various diseases, but its regulatory mechanism on ICH remains unclear. In this study, we investigated the protective effects and mechanisms of baicalin in ICH using an ICH mouse model. ICH mouse model was established by injection of collagenase type IV into intracranial in C57BL/6 mice. Neurological function was evaluated by neurological severity scores and the rotarod test. Hemorrhagic foci of brain was evaluated by TTC and hematoxylin−eosin staining. Iron ion deposition in brain was detected by Prussian blue staining. Ferroptosis was evaluated by measuring expression of FTH-1, SLC7A11, GPX4, and TFRC, as well as detecting iron content and levels of glutathione (GSH) and malondialdehyde (MDA). GPX4 expression and apoptosis of brain were detected by immunofluorescence staining and TUNEL assay. Results showed that baicalin improved neurological function and reduced the area of hemorrhagic foci of brain in ICH mouse model. Baicalin decreased iron ion deposition, inhibited ferroptosis and apoptosis, and upregulated GPX4 in brain of ICH mouse model. Moreover, baicalin increased AKT1 phosphorylation and the protein level of Nrf2 in brain of ICH mouse model. Notably, AKT1 inhibitor LY294002 and Nrf2 inhibitor reversed the effects of baicalin on the activation of AKT1/Nrf2/GPX4 axis and the inhibition of ferroptosis in brain of ICH mouse model. Collectively, we demonstrated that baicalin promotes ICH recovery by inhibiting ferroptosis in brain tissue through activation of AKT/Nrf2/GPX4 axis. These results may provide new insights for the study of baicalin in the treatment of ICH.
研究领域:
神经病学
·
分子医学
·
药理学
·
自由基生物学
·
脑血管病
·
神经保护机制
✓ 已验证
产品关联
DOI
PubMed
高影响因子
ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS
·
2025
·
IF 3
Mengying Jin,Xiao Chen,Lanzhuoying Zheng,Yuanyuan Peng,Mingying Lin,Ke Liang,Xinran Liu,Zihan Xu,Yiming Yang,Baozhu Wei,Jing Wan
Background Astaxanthin (ASX), a fat-soluble carotenoid mainly sourced from Haematococcus pluvialis, shows promise for clinical applications in chronic inflammatory diseases. This study investigates whether ASX can mitigate atherosclerosis (AS) by modulating macrophage ferroptosis and provides astaxanthin-loaded polylactic acid-glycolic acid nanoparticles (ASX-PLGA NPs) as comparison. Method ApoE−/− mice were fed a high-fat diet with ASX or statin intervention. Plaque area, lipid aggregation, collagen content, and ferroptosis-related indicators were assessed. Moreover, ASX-PLGA NPs were synthesized and characterized and were used to pretreat macrophages induced with oxidized low-density lipoprotein (ox-LDL). Indicators linked to ferroptosis and oxidative stress were detected. Finally, the expression of nuclear factor erythroid -related factor 2 (NRF2) was evaluated. Results ASX intervention significantly delayed the progression of AS plaques, characterized by reductions in plaque area and increased collagen fibers. The observed improvements in AS were consistent with statins. ASX-PLGA NPs demonstrate good safety and stability and have better therapeutic effects than ASX alone. Indicators linked to ferroptosis and oxidative stress were significantly improved in groups containing ASX in vivo and vitro. Additionally, ASX facilitated the nuclear translocation of NRF2, which could be attenuated with ML385, a specific inhibitor of NRF 2. Conclusion ASX-PLGA NPs have better therapeutic effects than ASX alone. The regulation of NRF2/SLC7A11/GPX4 represents a novel mechanism by which ASX can counteract ferroptosis and impede AS progression.
研究领域:
医学
·
药理学
·
生物化学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
INFLAMMATION RESEARCH
·
2025
·Vol. 74
·期 1
·1-19
·
IF 5.4
Weng Xiuhong,Wang Simin,Wang Qing,Wei Mingbo,Cheng Bo
Background Primary Sjögren’s syndrome (pSS) is an autoimmune disease characterized by xerostomia and autoimmune sialadenitis. Interferon-γ (IFN-γ) induces ferroptosis in salivary gland epithelial cells (SGECs), leading to salivary gland (SG) hypofunction. We previously demonstrated the beneficial effects of melatonin (MLT) in alleviating SG dysfunction and inflammation in a pSS animal model. However, the precise underlying mechanism remains unclear. Methods Female NOD/ltj and ICR mice were used as the pSS mouse model and control group, respectively. MLT was administered via intraperitoneal injection to NOD/ltj mice to detect its effect on ferroptosis in SGs. Primary human SGECs and A253 cells were treated with IFN-γand ferroptosis inducers, with or without MLT. Results Exogenous MLT alleviated pathological SG alterations and promoted saliva production through inhibiting SGEC ferroptosis. MLT inhibited SGEC ferroptosis induced by IFN-γ and ferroptosis inducers via nuclear factor erythroid 2-related factor 2/heme oxygenase-1/glutathione peroxidase 4 (NRF2/HO-1/GPX4) pathway activation. Moreover, MLT suppressed the nuclear factor-kappa B (NF-κB) pathway, which is triggered by ferroptosis in SGECs. Nevertheless, ML385-mediated NRF2 inhibition abrogated the antiferroptotic protective effects of MLT on SGECs. Conclusions MLT inhibits SGEC ferroptosis through NRF2/HO-1/GPX4 pathway activation and thus attenuates ferroptosis-triggered NF-κB activity. Melatonin represents a potential therapeutic approach for pSS owing to its capacity to regulate ferroptosis.
研究领域:
免疫学
·
细胞生物学
·
医学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）