Frontiers in Cell and Developmental Biology
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2021
·
IF 6.684
Zhu Yiming,Zhang Chihao,Huang Mingzhe,Lin Jiayun,Fan Xiao,Ni Tao
Hepatic stellate cells (HSCs) are activated by inflammatory mediators to secrete extracellular matrix for collagen deposition, leading to liver fibrosis. Ferroptosis is iron- and lipid hydroperoxide-dependent programmed cell death, which has recently been targeted for inhibiting liver fibrogenic processes. Tripartite motif-containing protein 26 (TRIM26) is an E3 ubiquitin ligase that functions as a tumor suppressor in hepatocellular carcinoma, while little is known about its function in liver fibrosis. In the present study, the differential expression of TRIM26 in normal and fibrotic liver tissues was examined based on both online databases and specimens collected from patient cohort. The effects of TRIM26 on HSCs ferroptosis were examined in vitro through evaluating cell proliferation, lipid peroxidation, and expression of key ferroptosis-related factors. In vivo function of TRIM26 in liver fibrosis was examined based on CCl4-induced mice model. We found that TRIM26 was downregulated in fibrotic liver tissues. The overexpression of TRIM26 inhibited HSCs proliferation, promoted lipid peroxidation, manipulated ferroptosis-related factor expressions, and counteracted the effect of iron inhibitor deferoxamine. Moreover, TRIM26 physically interacted with solute carrier family-7 member-11 (SLC7A11), a critical protein for lipid reactive oxygen species (ROS) scavenging, and mediated its ubiquitination. In addition, TRIM26 overexpression induced HSCs ferroptosis and mitigated CCl4-induced liver fibrosis in mice. In conclusion, TRIM26 promotes HSCs ferroptosis to suppress liver fibrosis through mediating the ubiquitination of SLC7A11. The TRIM26-targeted SLC7A11 suppression can be a novel therapeutic strategy for liver fibrosis.
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Nanoscale
·
2021
·Vol. 13
·期 9
·4855-4870
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IF 7.79
Qifang Chen,Xianbin Ma,Li Xie,Wenjie Chen,Zhigang Xu,Erqun Song,Xiaokang Zhu,Yang Song
Ferroptosis therapy, which applies ferroptotic inducers to produce lethal lipid peroxidation and induce the death of tumor cells, is regarded as a promising therapeutic strategy for cancer treatment. However, there is still a challenge regarding how to increase reactive oxygen species (ROS) accumulation in the tumor microenvironment (TME) to enhance antitumor efficacy. Herein, we designed a nanosystem coated with the FDA approved poly(lactic-co-glycolic acid) (PLGA) containing ferrous ferric oxide (Fe3O4) and chlorin E6 (Ce6) for synergistic ferroptosis-photodynamic anticancer therapy. The Fe3O4-PLGA-Ce6 nanosystem can dissociate in the acidic TME to release ferrous/ferric ions and Ce6. Then, the Fenton reaction between the released ferrous/ferric ions and intracellular excess hydrogen peroxide can occur to produce hydroxyl radicals (˙OH) and induce tumor cell ferroptosis. The released Ce6 can increase the generation and accumulation of ROS under laser irradiation to offer photodynamic therapy, which can boost ferroptosis in 4T1 cells. Moreover, magnetic monodisperse Fe3O4 loading provides excellent T2-weighted magnetic resonance imaging (MRI) properties. The Fe3O4-PLGA-Ce6 nanosystem possesses MRI ability and highly efficient tumor suppression with high biocompatibility in vivo due to the synergism of photodynamic and ferroptosis antitumor therapies.
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ACS Applied Materials & Interfaces
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2020
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IF 8.758
Longfa Kou,Rui Sun,Xinyu Jiang,Xinlu Lin,Huirong Huang,Shihui Bao,Youting Zhang,Chao Li,Ruijie Chen,Qing Yao
Tumor cells usually display metabolic, genetic, and microenvironment-related alterations, which are beneficial to tumor proliferation, tumor development, and resistance occurrence. Many transporters and enzymes, including ATB0,+, xCT, and matrix metalloproteinases (MMPs), are involved in the altered cell metabolism and tumor microenvironment and often abnormally upregulated in malignant tumors. Meanwhile, these dysregulated transporters and enzymes provide targets not only for a pharmacological blockage to suppress tumor progress but also for tumor-specific delivery. Although transporters and MMPs have been widely reported for antitumor drug delivery, the feasibility of utilizing two strategies has never been elucidated yet. Herein, we developed an MMP2-activated and ATB0,+-targeted liposome with doxorubicin and sorafenib (DS@MA-LS) loaded for optimal tumor drug delivery for cancer therapy. DS@MA-LS was designed to prolong blood circulation and deshield the PEG shell from MMP2 cleavage to expose lysine and target overexpressed ATB0,+ for enhanced tumor distribution and cancer cellular uptake. Besides the anticancer effects of loaded drugs, the endocytosed liposomes could further increase ROS production and suppress the antioxidant system to amplify oxidative stress. As expected, DS@MA-LS displayed enhanced targeted drug delivery to tumor sites with the MMP2-controlled ligand exposure and ATB0,+-mediated uptake. More importantly, DS@MA-LS successfully inhibited the tumor growth and cancer cell proliferation both in vitro and in vivo by enhancing apoptosis and ferroptosis, which thanks to the increased ROS generation and impaired GSH synthesis synergistically amplified oxidative stress. Our results suggested that the tumor microenvironment-responsive, multistaged nanoplatform, DS@MA-LS, has excellent potential for optimal drug delivery and enhanced cancer treatment.
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ACS Applied Materials & Interfaces
·
2024
·
IF 8.3
Shiyan Li,Xuwei Shang,Haiya Lou,Zixu Wang,Yihe Qiu,Shanshan Xiang,Fangying Yu,Hong Yuan
The immunosuppressive tumor environment, characterized by elevated redox levels, significantly impairs the effectiveness of oxidation and the immune response. Here, an electron-accepting-inspired glycopolymer-based nanoreactor (chitosan-grafted nitrobenzene nanoparticles) CNP employing hypoxia-activated group nitrobenzene was constructed to realize cascade bilateral regulation of ferroptosis and immune activation by intervening antioxidant systems. The as-prepared CNP could consume nicotinamide adenine dinucleotide phosphate (NADPH) in the hypoxia-response process, allowing it to be involved in the recycling of glutathione (GSH) and thioredoxin (Trx). This ultimately affects redox homeostasis, leading to reduced GSH levels, increased reactive oxygen species (ROS), and inhibition of (glutathione peroxidase 4) Gpx4. By taking advantage of the sensitivity difference between tumor cells and dendritic cells (DCs) to the ferroptosis inducer erastin (Er) based on varying xCT expression levels, we developed Er-loaded nanoparticles CNP/Er. These nanoparticles not only enhance ferroptosis in 4T1 cells through Gpx4 inhibition by CNP but also promote DC maturation by utilizing CNP’s hypoxia-responsive mechanism to increase ROS levels. The CNP/Er was believed to be an ideal candidate for bilateral regulation of ferroptosis and immune activation in one nanoreactor.
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Open Medicine
·
2025
·Vol. 20
·期 1
·
IF 1.6
Xi Yan,Yinghao Niu,Yaojie Wang,Sisi Wei,Lina Han,Zhongyu Guo,Lianmei Zhao,Feng Gao
Purpose
This study aims to investigate the role and mechanism of p -hydroxyl cinnamaldehyde (CMSP) in triggering ferroptosis of small cell lung cancer (SCLC) cells.
Methods
The impact of CMSP on ferroptosis in H1688 and SW1271 cells was assessed through cell experiments and biological information analysis. Moreover, the expression of heme oxygenase 1 (HMOX1) in SCLC tissue was examined.
Results
Following CMSP treatment, a concentration-dependent increase in cell death was observed, and differentially expressed genes were found to be associated with ferroptosis. CMSP notably facilitated ferroptosis events, such as elevated levels of reactive oxygen species (ROS), Fe 2+ , malondialdehyde (MDA), transferrin receptor 1 (TFR1), divalent metal transporter 1 (DMT1), and decreased levels of glutathione (GSH), solute carrier family 7 member 11 (SLC7A11), and glutathione peroxidase 4 (GPX4). Furthermore, CMSP promoted mitochondrial dysfunction, manifested as reduced mitochondrial volume, increased membrane density, elevated mitochondrial ROS, and decreased mitochondrial membrane potential. Consistently, the mitochondrial-targeted antioxidant Mito-TEMPO reversed CMSP-induced ferroptosis. Expression of the HMOX1 gene was markedly increased under CMSP treatment, while lower expression was observed in cancer tissue compared to adjacent tissue.
Conclusion
CMSP triggers mitochondrial dysfunction via HMOX1 activation, leading to ferroptosis in SCLC cells, underscoring its potential as a therapeutic agent for SCLC.
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CHEMICAL ENGINEERING JOURNAL
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2024
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IF 13.3
Xinxin Wang,Jianmin Zhou,Yanlin Zhu,Can Yu,Di Sun,Yuanfei Yao,Lili Feng,Piaoping Yang,Yang Zhou
Radiotherapy (RT) represents a cornerstone therapeutic approach in clinical practice for locally control of hepatocellular carcinoma (HCC). However, its efficacy in treating liver cancer is significantly hampered by radiation resistance, which attributed to the insufficient reactive oxygen species (ROS) generation within the tumor microenvironment (TME). To augment RT efficacy, we have developed a novel radiosensitizer termed PTFM. The compound has the features of meso -tetra (4-carboxyphenyl) porphine (TCPP) porphyrin metal–organic frameworks (MOF, PCN-224(Fe)) co-doped with high-atomic element Ta. Under X-ray excitation, the porous PTFM acts as a proficient radio-sensitization, absorbs X-ray energy to promote hydroxyl radicals generation for RT, thereby disrupting the redox balance and intensifying the cytotoxic effect on tumor cells. The incorporation of Fe 3+ into the macrocycle of TCPP within the MOFs shell, facilitates the reactions with GSH and H 2 O 2 in the TME, leads to ROS production that promotes ferroptosis and apoptosis, while also releases O 2 to alleviate tumor hypoxia. Furthermore, PTFM with thermo-metal serves as a dual-mode MR/CT imaging contrast agent, enabling precise RT monitoring and imaging guidance. In conclusion, the radiosensitizer we developed integrates dual-mode imaging capabilities and enhances RT sensitization for HCC through ROS-induced cell apoptosis and ferroptosis, thereby ameliorating tumor hypoxia.
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Marine Drugs
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2025
·Vol. 23
·期 1
·49
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IF 5.4
Zi-Han Xu,Ming-Min Xie,Chun-Lan Xie,Xian-Wen Yang,Jun-Song Wang
Neuroinflammation and neuronal cell death are leading causes of death in the elderly and underlie various neurodegenerative diseases. These diseases involve complex pathophysiological mechanisms, including inflammatory responses, oxidative stress, and ferroptosis. Compounds derived from deep-sea fungi exhibit low toxicity and potent neuroprotective effects, offering a promising source for drug development. In this study, we isolated 44 natural products from deep-sea-derived fungi and identified isobisvertinol (17) as a compound with anti-inflammatory and ferroptosis-inhibiting effects. Using LPS-induced microglial inflammation and RSL3-induced neuronal ferroptosis models, we found that17targets TLR4 to provide neuroprotection. Molecular docking studies revealed that17inhibits TLR4 activation by occupying the hydrophobic pocket at the TLR4-MD2 binding site. Additionally,17suppresses TLR4, reducing p38 MAPK phosphorylation, and inhibits ferroptosis by decreasing lipid peroxidation and modulating mitochondrial membrane potential. Metabolomic analysis showed that17rescues alterations in multiple metabolic pathways induced by RSL3 and increases levels of antioxidant metabolites, including glutamine, glutamate, and glutathione. In summary, our results indicate that isobisvertinol (17) targets TLR4 in neural cells to reduce inflammation and inhibit p38 MAPK phosphorylation, while regulating metabolic pathways, mainly GSH synthesis, to provide antioxidant effects and prevent ferroptosis in neurons.
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EUROPEAN JOURNAL OF MEDICAL RESEARCH
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2024
·Vol. 29
·期 1
·1-14
·
IF 2.8
Zhao Xun,Yuan WenQiang,Yang LiuChan,Yan Fang,Cui DeJun
Background Worldwide, ulcerative colitis (UC) is becoming increasingly fast growing. Ginsenoside Rh2 has been reported to alleviate UC. However, the latent biological mechanism of Rh2 in the treatment of UC remains uncertain. In this study, the goal was to determine the therapeutic effect of Rh2 on dextran sulfate sodium (DSS)-induced UC. Methods A DSS-induced UC mouse model was established and divided into 7 groups for Rh2 gavage and/or miR-125a-5p lentivirus injection (n = 10 per group). Colonic specimens were collected for phenotypic and pathological analysis. miR-125a-5p and specific protein 1 (SP1) expression, inflammation-related factors IL-6 and IL-10, and apoptosis were detected in mice. Human normal colon epithelial cell line NCM460 was treated with H 2 O 2 and ferric chloride hexahydrate to construct an in vitro cell model of colitis and induce ferroptosis. Independent sample t-test was used to compare cell proliferation, cell entry, apoptosis, and oxidative stress between the two groups. One way analysis of variance combined with the least significant difference t test was used for comparison between groups. Multiple time points were compared by repeated measurement analysis of variance. Results DSS-induced UC mice had significantly decreased body weight, increased disease activity index, decreased colon length, and decreased miR-125a-5p expression (all P < 0.05). In the DSS-induced mouse model, the expression of miR-125a-5p rebounded and ferroptosis was inhibited after Rh2 treatment (all P < 0.05). Inhibition of miR-125a-5p or upregulation of SP1 expression counteracted the protective effects of Rh2 on UC mice and ferroptosis cell models (all P < 0.05). Conclusions Rh2 mitigated DSS-induced colitis in mice and restrained ferroptosis by targeting miR-125a-5p. Downregulating miR-125a-5p or elevating SP1 could counteract the protective impacts of Rh2 on ferroptotic cells. The findings convey that Rh2 has a latent application value in the treatment of UC. Graphical Abstract
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BIOCHEMICAL PHARMACOLOGY
·
2025
·
IF 5.6
Jiani Zhan,Yijia Chen,Yuying Liu,Yunqiu Chen,Zhiyao Li,Xuewen Li,Zhenning He,Fangzhou Meng,Xiaoyang Qian,Lili Yang,Qing Yang
Ferroptosis is a type of cell death marked by iron-dependent lipid peroxide accumulation. Indoleamine 2,3-dioxygenase 1 (IDO1), a key enzyme in the catabolism of tryptophan through kynurenine pathway, participates in the development of multiple tumor types. However, the role of IDO1 in tumor ferroptosis is unclear. In this study, we identified IDO1 as a key regulator of ferroptosis in lung cancer. With Erastin-treated lung cancer cells, we found that IDO1 inhibited ferroptosis, reduced the generation of lipid peroxide and ROS. Mechanistically, IDO1 promoted the expression of nuclear factor erythroid 2-related factor 2 (NRF2) through activating aryl hydrocarbon receptor (AhR) pathway. IDO1 up-regulated the expression of solute carrier family 7 member 11 (SLC7A11) and the activity of pentose phosphate pathway (PPP) via AhR-NRF2 axis, promoted the production of reduced nicotinamide adenine dinucleotide phosphate (NADPH) and glutathione (GSH), thereby inhibiting ferroptosis. Moreover, combined treatment with IDO1 inhibitor and Erastin inhibited tumor growth, down-regulated SLC7A11 expression and PPP activity, promoted tumor ferroptosis in lung cancer-bearing mice. In conclusion, this study revealed the function of IDO1 in lung cancer ferroptosis and provided a new strategy for lung cancer therapy.
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JOURNAL OF COLLOID AND INTERFACE SCIENCE
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2024
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IF 9.4
Weijuan Zou,Feng Gao,Zheying Meng,Xiaojun Cai,Wu Chen,Yuanyi Zheng,Tao Ying,Longchen Wang,Jianrong Wu
Ferroptosis is characterized by the lethal accumulation of lipid reactive oxygen species (ROS), which has great potential for tumor therapy. However, developing new ferroptosis-inducing strategies by combining nanomaterials with small molecule inducers is important. In this study, an enzyme-gated biodegradable natural-product delivery system based on lactate oxidase (LOD)-gated biodegradable iridium (Ir)-doped hollow mesoporous organosilica nanoparticles (HMONs) loaded with honokiol (HNK) (HNK@Ir-HMONs-LOD, HIHL) is designed to enhance ferroptosis in colon tumor therapy. After reaching the tumor microenvironment, the outer LOD dissociates and releases the HNK to induce ferroptosis. Moreover, the released dopant Ir 4+ and disulfide-bridged organosilica frameworks deplete intracellular glutathione (GSH), which is followed by GSH-mediated Ir(IV)/Ir(III) conversion. This leads to the repression of glutathione peroxidase 4 (GPX4) activity and decomposition of intratumoral hydrogen peroxide (H 2 O 2 ) into hydroxyl radicals (•OH) by Ir 3+ -mediated Fenton-like reactions. Moreover, LOD efficiently depletes lactic acid to facilitate the generation of H 2 O 2 and boost the Fenton reaction, which in turn enhances ROS generation. With the synergistic effects of these cascade reactions and the release of HNK, notable ferroptosis efficacy was observed both in vitro and in vivo. This combination of natural product-induced and lactic acid-responsive sequential production of H 2 O 2 as well as the consumption of glutathione may provide a new paradigm for achieving effective ferroptosis-based cancer therapy.
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CHEMICAL ENGINEERING JOURNAL
·
2024
·
IF 13.3
Shunying Liu,Yanhai Feng,Qianxiang Meng,Xiaoyu Wang,Yi Liang,Guihong Yang,Yongpeng Su,Ke Zhang,Chao Qi,Kaiyong Cai,Xia Lei
Wound infections present a significant clinical challenge, as the antibiotics commonly utilized in treating infected wounds confront the pressing issue of bacterial resistance. Consequently, it is imperative to develop antibacterial materials that can diminish reliance on antibiotics for effective management of such infections. In this study, we introduce a novel metal-polyphenol nanoplatform (designated as ICG@Fe-Qu) that synergistically integrates photothermal therapy (PTT), photodynamic therapy (PDT), chemodynamic therapy (CDT), and ferroptosis for the treatment of infected wounds. ICG@Fe-Qu is constructed through one-step assembly of quercetin (Qu), Fe 2+ and indocyanine green (ICG) in an aqueous solution. Upon exposure to near-infrared (NIR) laser irradiation, ICG@Fe-Qu generates localized heat for PTT, which disrupts bacterial membranes and facilitates iron ion penetration into bacterial interiors. Concurrently, ICG produces reactive oxygen species (ROS) under NIR irradiation for PDT applications. Combined with Fe-mediated Fenton reaction to generate hydroxyl radicals for CDT, substantial ROS is generated to induce lipid peroxidation ultimately leading to bacterial ferroptosis. Importantly, both in vivo and in vitro experiments demonstrate robust bactericidal activity of ICG@Fe-Qu against Staphylococcus aureus and Escherichia coli , along with efficient eradication of bacterial biofilms. Furthermore, ICG@Fe-Qu enhances fibroblast migration and accelerates wound healing processes, indicating its promising potential for treating infected wounds in clinics.
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ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY
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2024
·
IF 6.2
Jinzhu Meng,Lilin Xiao,Qiuye Li,Ling Gong,Ping Luo,Yuanyuan Zhao,Shuilian Wang
Di-(2-ethylhexyl) phthalate (DEHP), an endocrine-disrupting chemical present in plasticized products, exerts strong modulation on the anatomy and function of the female reproductive system. However, the potential mechanisms underlying DEHP-induced regulation of prepubertal female reproductive toxicity have not yet been elucidated. Therefore, this study was designed to elucidate the molecular mechanism of ovarian injury induced by DEHP exposure in mice. Elevated serum mono-2-ethylhexyl phthalate (MEHP) concentrations, decreased levels of ovarian hormones (E2 and P4), and observed ovarian injury were found after DEHP exposure. Ovarian transcriptome analysis revealed significant alterations in ferroptosis-associated gene expression, with potential regulation by Nrf2. Subsequent analysis of ferrous iron, malondialdehyde (MDA), Western blotting, and immunofluorescence of the ovaries confirmed the RNA-seq findings. Transcriptome analysis of granulosa cells revealed a direct or indirect regulatory relationship between Nrf2 and downstream ferroptosis-related proteins following MEHP exposure. Further experiments demonstrated that ferrostatin-1 attenuated MEHP-induced ferroptosis in granulosa cells. Additionally, Nrf2 stabilization and accumulation in the nucleus of granulosa cells were observed following MEHP treatment. RNAi-mediated knockdown of Nrf2 exacerbated MEHP-induced ferroptosis in granulosa cells. This evidence indicates that DEHP exposure induces ferroptosis through regulation of the Nrf2-mediated signaling pathway in mouse ovaries, laying the groundwork for future studies aiming to develop therapeutic strategies against DEHP toxicity.
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