Journal of Functional Biomaterials
·
2024
·Vol. 15
·期 8
·205
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IF 5
Zihan Zhuo,Chunfang Yin,Zhenqing Zhang,Yumeng Han,Haoye Teng,Qi Xu,Changming Li
The issue of bacterial resistance is an escalating problem due to the misuse of antibiotics worldwide. This study introduces a new antibacterial mechanism, the ferroptosis-like death (FLD) of bacteria, and an approach to creating green antibacterial nano-reactors. This innovative method leverages natural iron-containing ovotransferrin (OVT) assembled into an organic skeleton to encapsulate low-concentration adriamycin (ADM) for synthesizing eco-friendly nano-reactors. FLD utilizes the Fenton reaction of reactive oxygen species and ferrous ions to continuously produce ·OH, which can attack the bacterial cell membrane and destroy the cell structure to achieve bacteriostasis. The OVT@ADM nano-reactors are nearly spherical, with an average diameter of 247.23 nm and uniform particle sizing. Vitro simulations showed that Fe3+in OVT@ADM was reduced to Fe2+by glutathione in the bacterial periplasmic space, which made the structure of OVT loose, leading to a sustained slow release of ADM from OVT@ADM. The H2O2continuously produced by ADM oxidized Fe2+through the Fenton reaction to produce ·OH and Fe3+. The results of the antibacterial assay showed that OVT@ADM had a satisfactory antibacterial effect againstS. aureus, and the inhibition rate was as high as 99.3%. The cytotoxicity results showed that the mitigation strategy significantly reduced the cytotoxicity caused by ADM. Based on the FLD mechanism, OVT@ADM nano-reactors were evaluated and applied to bacteriostasis. Therefore, the novel antibacterial mechanism and OVT@ADM by the green synthesis method have good application prospects.
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Drug Design Development and Therapy
·
2024
·
IF 4.7
Yong-Yu Yang,Rong-Rong Deng,Da-Xiong Xiang
Background Ferroptosis plays a crucial role in the occurrence and development of cerebral ischemia-reperfusion (I/R) injury and is regulated by mitogen-activated protein kinase 1/2 (ERK1/2). In China, Naodesheng Pills (NDSP) are prescribed to prevent and treat cerebrosclerosis and stroke. However, the protective effects and mechanism of action of NDSP against cerebral I/R-induced ferroptosis remain unclear. We investigated whether NDSP exerts its protective effects against I/R injury by regulating ferroptosis and aimed to elucidate the underlying mechanisms.Methods The efficacy of NDSP was evaluated using a Sprague-Dawley rat model of middle cerebral artery occlusion and an in vitro oxygen-glucose deprivation/reoxygenation (OGD/R) model. Brain injury was assessed using 2,3,5-triphenyltetrazolium chloride (TTC), hematoxylin and eosin staining, Nissl staining, and neurological scoring. Western blotting was performed to determine the expression levels of glutathione peroxidase 4 (GPX4), divalent metal-ion transporter-1 (DMT1), solute carrier family 7 member 11 (SLC7A11), and transferrin receptor 1 (TFR1). Iron levels, oxidative stress, and mitochondrial morphology were also evaluated. Network pharmacology was used to assess the associated mechanisms.Results NDSP (1.08 g/kg) significantly improved cerebral infarct area, cerebral water content, neurological scores, and cerebral tissue damage. Furthermore, NDSP inhibited I/R- and OGD/R-induced ferroptosis, as evidenced by the increased protein expression of GPX4 and SLC7A11, suppression of TFR1 and DMT1, and an overall reduction in oxidative stress and Fe2+ levels. The protective effects of NDSP in vitro were abolished by the GPX4 inhibitor RSL3. Network pharmacology analysis revealed that ERK1/2 was the core target gene and that NDSP reduced the amount of phosphorylated ERK1/2.Conclusion NDSP exerts its protective effects against I/R by inhibiting cerebral I/R-induced ferroptosis, and this mechanism is associated with the regulation of ferroptosis via the ERK1/2 signaling pathway.
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BIOMATERIALS
·
2024
·
IF 12.8
Jingjing Shen,Kai Feng,Jing Yu,Yaxuan Zhao,Ruifang Chen,Hehua Xiong,Yiling Ruan,Zhengtao Xu,Tao Zhang,Xiaolian Sun
Ferroptosis is an iron-dependent form of programmed cell death with the potential to reverse traditional cancer therapy resistance. The combination of ferroptosis with chemotherapy, photodynamic therapy and X-ray therapy has demonstrated remarkably improved therapeutic efficiency. Radiopharmaceutical therapy (RPT) is an emerging approach that achieves precise radiation to diseased tissues via radionuclide delivery. However, insufficient accumulation and retention of therapeutic radiopharmaceuticals in tumor region as well as cancer radioresistance impact treatment efficacy. Here, a nanoassembly of renal clearable ultrasmall iron nanoparticles (USINPs) and 131 I-aPD-L1 is prepared via the affinity of fluorophenylboronic acid modified on the USINPs with 131 I-aPD-L1. The 150 nm USINAs( 131 I-aPD-L1) nanoassembly is stable in blood circulation, effectively targets to the tumor and disassembles in the presence of ATP in the tumor microenvironment. Both in vitro and in vivo experiments prove that USINPs-induced ferroptosis boosted the tumor radiosensitization to 131 I while 131 I-mediated RPT further enhanced ferroptosis. Meanwhile, the immunogenic cell death caused by RPT and ferroptosis combined with PD-L1 immune checkpoint blockade therapy exhibits a strong antitumor immunity. This study provides a novel way to improve the tumor accumulation of ferroptosis inducer and radiopharmaceuticals, insights into the interaction between RPT and ferroptosis and an effective SPECT-guided ferroptosis-enhanced radio-immunotherapy.
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Journal of Advanced Research
·
2024
·
IF 11.4
Guiqin Huang,Yawen Cai,Menghui Ren,Xiaoyu Zhang,Yu Fu,Run Cheng,Yingdi Wang,Mingxing Miao,Lingpeng Zhu,Tianhua Yan
Introduction Triple-negative breast cancer (TNBC) is the primary cause of breast cancer-induced death in women. Literature has confirmed the benefits of Salidroside (Sal) in treating TNBC. However, the study about potential therapeutic targets and mechanisms of Sal-anchored TNBC remains limited. Objective This study was designed to explore the main targets and potential mechanisms of Sal against TNBC. Methods Network pharmacology, bioinformatics, and machine learning algorithm strategies were integrated to examine the role, potential targets, and mechanisms of the Sal act in TNBC. MDA-MB-231 cells and tumor-bearing nude mice were chosen for in vitro and in vivo experimentation. Cell viability and cytotoxicity were determined using CCK-8, LDH test, and Calcein-AM/PI staining. Antioxidant defense, lipid peroxidation, and iron metabolism were explored using glutathione, glutathione peroxidase, malondialdehyde (MDA), C11-BODIPY 581/591 probe, and FerroOrange dye. Glutathione peroxidase 4 (GPX4) or stearoyl-CoA desaturase 1 (SCD1) overexpression or nuclear receptor co-activator 4 (NCOA4) deficiency was performed to demonstrate the mechanism of Sal on TNBC. Results The prediction results confirmed that 22 ferroptosis-related genes were identified in Sal and TNBC, revealing that the potential mechanism of the Sal act on TNBC was linked with ferroptosis. Besides, these genes were mainly involved in the mTOR, PI3K/AKT, and autophagy signaling pathway by functional enrichment analysis. The in vitro validation results confirmed that Sal inhibited TNBC cell proliferation by modulating ferroptosis via elevation of intracellular Fe 2+ and lipid peroxidation. Mechanistically, Sal sensitized TNBC cells to ferroptosis by inhibiting the PI3K/AKT/mTOR axis, thereby suppressing SCD1-mediated lipogenesis of monounsaturated fatty acids to induce lipid peroxidation, additionally facilitating NCOA4-mediated ferritinophagy to increase intracellular Fe 2+ content. The GPX4 or SCD1 overexpression or NCOA4 deficiency results further supported our mechanistic studies. In vivo experimentation confirmed that Sal is vital for slowing down tumor growth by inducing ferroptosis. Conclusions Overall, this study elucidates TNBC pathogenesis closely linked to ferroptosis and identifies potential biomarkers in TNBC. Meanwhile, the study elucidates that Sal sensitizes TNBC to ferroptosis by SCD1-mediated lipogenesis and NCOA4-mediated ferritinophagy, regulated by PI3K/AKT/mTOR signaling pathways. Our findings provide a theoretical basis for applying Sal to treat TNBC.
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BIOMATERIALS
·
2025
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IF 12.9
Yan Gao,Zilin Song,Wenxin Gan,Xue Zou,Yaning Bai,Xiuli Zhao,Dawei Chen,Mingxi Qiao
Despite the promise of ferroptosis in cancer therapy, selectively inducing robust ferroptosis in cancer cells remains a significant challenge. In this study, manipulation of fatty acids β-oxidation (FAO) by combination of mild photodynamic therapy (PDT) and inhibition of triglycerides (TGs) synthesis was found to induce robust and iron-independent ferroptosis in cancer cells with dysregulated lipid metabolism for the first time. To achieve that, TGs synthesis inhibitor of xanthohumol (Xan) and FAO initiator of tetrakis (4-carboxyphenyl) porphyrin (TCPP) were co-delivered by a nanoplexes composed of pH-responsive amphiphilic lipopeptide C 18 -pHis 10 and DSPE-PEG 2000 . TCPP was found to rapidly increase the intracellular ROS under laser irradiation without inducing antioxidant response and apoptosis, activating the AMPK in cancer cells and accelerating mitochondrial FAO. Xan fueled the mitochondrial FAO with substrates by suppressing the conversion of fatty acids (FAs) to TGs. This also led to augmented intracellular polyunsaturated fatty acids (PUFAs) and PUFAs-phospholipids levels, increasing the intrinsic susceptibility of cancer cells to lipid peroxidization. As a result, the excessive ROS generated from the sustained mitochondrial FAO caused remarkably lipid peroxidation and ultimately ferroptosis. Collectively, our study provides a new approach to selectively induce iron-independent ferroptosis in cancer cells by taking advantage of dysregulated lipid metabolism.
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ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY
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2022
·
IF 7.129
Wenyu Miao,Lingling He,Yong Zhang,Xiaoyu Zhu,Yangming Jiang,Pengpeng Liu,Tao Zhang,Chunqi Li
Glucocorticoids (GCs) have been widely detected in the aquatic system. However, the hazardous effects of GCs on aquatic organisms were underestimated, and the mechanisms of GCs-induced toxic effects in fish were largely unknown. The zebrafish larvae at 3 dpf were exposed to dexamethasone (DEX) for 48 h, and the toxic effects and the underlying mechanisms were investigated in the current study. The T cells were ablated in zebrafish larvae after being treated with 1, 3, 10, 30 and 100 μM of DEX for 48 h. In addition, osteoporosis was induced and the regeneration of the caudal fin was inhibited, by 48 h-exposure to 10, 30 and 100 μM of DEX. The transcriptomic analysis, biochemical parameters and gene expression profiles revealed that ferroptosis possibly contributed to the DEX-induced toxic effects in zebrafish larvae. Finally, Fer-1 treatment partially attenuated the DEX-induced T cell ablation, but not osteoporosis in zebrafish larvae. Taken together, the current study proved the toxic effects of DEX on zebrafish larvae, and elucidated that ferroptosis was involved in DEX-induced toxicity, providing strong evidence for the toxic effects of GCs on aquatic organisms.
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MOLECULAR PHARMACEUTICS
·
2022
·
IF 5.364
Ying Chen,Xiaoming Liao,Pei Jing,Liangkui Hu,Zengqiu Yang,Yongchao Yao,Chunyan Liao,Shiyong Zhang
As the most common subtype in ovarian malignancies, high-grade serous ovarian cancer (HGSOC) made less therapeutic progress in past decades due to the lack of effective drug-able targets. Herein, an effective linoleic acid (LA) and glucosamine (GlcN) hybrid (LA–GlcN) was synthesized for the treatment of HGSOC. The GlcN was introduced to recognize the glucose transporter 1 (GLUT 1) overexpressed in tumor cells to enhance the uptake of LA–GlcN, and the unsaturated LA was employed to trigger ferroptosis by iron-dependent lipid peroxidation. Since the iron content of HGSOC was ∼5 and 2 times, respectively, higher than that of the normal ovarian cells and low-grade serous ovarian cancer cells, these excess irons make them a good target to enhance the ferroptosis of LA–GlcN. The in vitro study demonstrated that LA–GlcN could selectively kill HGSOC cells without affecting normal cells; the in vivo study revealed that LA–GlcN at the dose of 50 mg kg–1 achieved a comparable tumor inhibition as doxorubicin hydrochloride (4 mg kg–1) while the overall survival of mice was extended largely due to the low toxicity, and when the dose was increased to 100 mg kg–1, the therapeutic outcomes could be improved further. This dietary hybrid which targets the excess endogenous iron to activate ferroptosis represents a promising drug for HGSOC treatment.
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JOURNAL OF CARDIOVASCULAR PHARMACOLOGY
·
2023
·Vol. 82
·期 2
·128-137
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IF 3
Fu Caihua,Yu Shengbo,Liu Zhiquan,Wang Jiayu,Liu Ping,Su Guohai
Six-phosphofructo-2-kinase/fructose-2, 6-bisphosphatase 2 (PFKFB2) is a key regulator of glycolytic enzyme. This study identified whether PFKFB2 can regulate myocardial ferroptosis in ischemia/reperfusion (I/R) injury. Mice myocardial (I/R) injury and H9c2 cells oxygen-glucose deprivation/reperfusion
(OGD/R) models were established. PFKFB2 expression was enhanced in I/R mice and OGD/R H9c2 cells. Overexpression of PFKFB2 improves heart function in I/R mice. Overexpression of PFKFB2 inhibits I/R and OGD/R-induced ferroptosis in mice and H9c2 cells. Mechanistically, overexpression of PFKFB2
activates the adenosine monophosphate–activated protein kinase (AMPK). AMPK inhibitor compound C reverses effect of PFKFB2 overexpression in reducing ferroptosis under OGD/R treatment. In conclusion, PFKFB2 protects hearts against I/R-induced ferroptosis through activation of the AMPK
signaling pathway.
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Materials Today Bio
·
2026
·
IF 11
Mian Yu,Yuanqi Liu,Jiayin Yu,Shengjie Sun,Yanling Chen,Yixuan Fang,Yuk Chin Angel Chung,Xuande Zhu,Hui Cai,Meiying Wu
Copper exerts opposing effects on immunogenic ferroptosis. • Driving PUFA remodeling, siC@CuPP overcomes copper-induced metabolic ferroptosis resistance. • Copper-mediated inhibition of extracellular GPX4 release is preserved in siC@CuPP. • siC@CuPP-mediated potent antitumor immunity suppresses primary tumors and distant metastasis. Ferroptosis is an immunogenic form of regulated cell death with considerable potential for cancer immunotherapy, yet its efficacy is frequently limited by adaptive resistance mechanisms. Here, we uncover a previously unrecognized bidirectional role of copper-based ferroptosis inducers in breast cancer. On the one hand, copper suppresses the release of extracellular GPX4, an immunosuppressive damage-associated molecular pattern, preserving the immunostimulatory effects of ferroptotic cell death. On the other hand, copper-induced ferroptotic stress activates carnitine palmitoyltransferase 1A (CPT1A)-dependent fatty acid oxidation, which limits polyunsaturated fatty acid (PUFA) availability and reduces ferroptosis susceptibility. To overcome this adaptive metabolic resistance, we developed siC@CuPP, a polyethylenimine-modified copper-doped polypyrrole nanocomplex that delivers Cpt1a siRNA while retaining the intrinsic ferroptosis-inducing activity of the CuPPy core. siC@CuPP efficiently silenced Cpt1a , inhibited fatty acid oxidation-driven PUFA consumption, promoted lipid remodeling, and impaired NADPH replenishment, thereby enhancing oxidative stress and ferroptosis sensitivity. Concurrently, copper-mediated suppression of extracellular GPX4 relieved ferroptosis-associated immunosuppression and facilitated dendritic cell activation. These coordinated effects established a positive feedback loop between immunogenic ferroptosis and antitumor immunity through interferon-γ–ACSL4 signaling. In an orthotopic 4T1 triple-negative breast cancer model, systemic administration of siC@CuPP elicited robust antitumor immune responses, significantly suppressing primary tumor growth and pulmonary metastasis. Collectively, this work identifies CPT1A-dependent metabolic adaptation and extracellular GPX4-mediated immunosuppression as two notable barriers to immunogenic ferroptosis and provides a coordinated strategy for overcoming both, thereby amplifying ferroptosis-driven cancer immunotherapy. Download: Download high-res image (577KB) Download: Download full-size image
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NANOTECHNOLOGY
·
2021
·Vol. 32
·期 39
·395605
·
IF 3.874
Rong Cai,Long Xiao,Jianghong Qiu,Lulu Zhao,Zhuoxin Li,Huixiang Ju,Mingzhong Sun,Wenkai Zhu,Zhirong Wang,Fengyi Du
Ferroptosis as an iron-dependent lipid peroxidation process causes sevely oxidative damage of cell, but lack of highly efficient and recycable antioxidant agents. To this end, cerium doped carbon dots (Ce-doped CDs) with radical scavenging activity were synthesized using a simple microwave-assisted hydrothermal carbonization. The resultant Ce-doped CDs exhibited an ultra-small size of only approximately 2.6 nm, excellent dispersion in water as well as optical performance. Taking advantage of inherent ultra-small size, Ce-doped CDs were endowed with high Ce3+/Ce4+ ratio, which significantly enhanced their radical scavenging activity. Meanwhile, the Ce-doped CDs with superior biocompatibility could enter cells quickly and then localized in the cytoplasm. As we expected, the Ce-doped CDs strongly protected cells from oxidative damage of erastin-mediated ferroptosis. These findings suggest that the as-prepared Ce-doped CDs have the potential to be antioxidant drugs against for ferroptosis-induced oxidative damage.
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EXPERIMENTAL CELL RESEARCH
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2023
·
IF 3.7
Mingmei Li,Li Li,Xiaoxiao Cheng,Longyu Li,Kaijia Tu
Background Ovarian cancer has been a worldwide health burden for women and its progression is highly hypoxia-independent. Here, we investigated the exact mechanisms by which hypoxia contributes to the malignant progression of ovarian cancer. Method MTT, transwell, colony formation, and scratch wound healing assays were carried out for cellular functions. The underlying mechanism by which hypoxia functions was explored by RNA-seq, enrichment analysis, western blotting, qRT-PCR, flow cytometry, ChIP, luciferase reporter, and ELISA. Finally, animal experiments including the xenograft model and tumor metastasis model were constructed to validate the role of SLC2A12 in vivo . Results Hypoxia treatment promoted the cell proliferation, mobility, and colony growth abilities of the two ovarian cancer cell lines HO-8910 and A2780. RNA-seq and enrichment analysis showed that SLC2A12 was hyper-expressed under hypoxia condition and it may be related to glutathione and lipid metabolism. Besides, the expression of SLC2A12 was negatively correlated with overall survival. Hypoxia suppressed ferroptosis by SLC2A12 because silencing SLC2A12 declined the cell viability of HO-8910 and A2780 cells under hypoxia conditions, while the ferroptosis inhibitor ferrostatin-1 (Fer-1) breached that result and upregulated the expression of glutathione peroxidase 4 (GPX4). Moreover, hypoxia increased the expression of hypoxia inducible factor 1 A (HIF-1A), and the accumulated HIF-1A binds to hypoxia inducible factor 1 B (HIF1B) to form HIF-1 complex, then promoted the binding of hypoxic response elements (HRE) to SLC2A12 promoter by HIF-1/HRE signal. Subsequently, SLC2A12 regulated glutathione metabolism and in turn inhibited ferroptosis. The animal experiments indicated that silencing SLC2A12 could significantly inhibit tumor growth and metastasis in vivo . Conclusion Hypoxia promoted ovarian cancer progression by upregulating SLC2A12 and then regulating glutathione metabolism to inhibit ferroptosis.
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FREE RADICAL BIOLOGY AND MEDICINE
·
2025
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IF 8.2
Zhenyu Yang,Ziming Wang,Jingsheng Huang,Meiqi Luo,Xinling Luo,Weiqi Zeng,Yingxin Gao,Fei Huang,Zhizhao Deng,Dongdong Yuan
Ischemia-reperfusion injury (IRI) remains the leading cause of early graft failure following liver transplantation (LT). Traditional paradigms have centered on hepatocyte death, yet the decisive contribution of liver sinusoidal endothelial cells (LSECs) as the first vascular barrier has long been overlooked. Here, single-cell RNA sequencing of human livers comparing normal controls with those exposed to transplantation-induced IRI, identified EMP1 as the most upregulated gene in LSECs. In LSECs and BRL3A hepatocytes subjected to hypoxia/reoxygenation (H/R), EMP1 silencing with an siRNA, ferroptosis modulation via ferrostatin-1 (Fer-1) or RSL3, and p38 signaling intervention using the p38 activator berberine chloride collectively revealed that EMP1 drives ferroptosis in LSECs in a p38-dependent manner. The results demonstrated that LSECs constituted the predominant hepatic endothelial population, whose numbers decline precipitously after transplantation. EMP1 emerged as the most markedly up-regulated gene in LSECs, correlating closely with the severity of injury. Silencing of EMP1 restored fenestral architecture, reduced VCAM-1 and E-selectin expression levels, suppressed Fe 2+ accumulation and lipid peroxidation, down-regulated ACSL4, and reinstated GPX4, thereby halving the hepatocyte death effects phenocopied by Fer-1 and reversed by RSL3, confirming that ferroptosis as the central mechanism. Furthermore, EMP1 exerted its effects solely via p38 signaling and its depletion selectively abolished p38 phosphorylation, whereas the p38 activator berberine chloride fully reinstated ferroptotic phenotypes and hepatocyte injury. Collectively, these data establish EMP1/p38-driven LSEC ferroptosis as a direct cause of hepatocyte damage, offering a fundamentally new perspective on the pathogenesis of h epatic ischemia reperfusion injury (HIRI) and a novel, potentially targeted therapeutic strategy for its prevention and treatment.
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