Redox Biology
·
2025
·
IF 11.9
Xue Shi,Yun Zhao,Hong-Yu Gao,Wei Yang,Jun Liao,Hui-Han Wang,Xiao-Tian Wang,Wei Yan
Diffuse large B cell lymphoma (DLBCL) is a common hematologic malignancy. NFS1 cysteine desulfurase, as a rate-limiting enzyme in the iron-sulfur cluster (ISC) biogenesis, has been reported to be associated with tumor progression. However, the role of NFS1 in DLBCL remains elusive. Here, we showed an upregulation of NFS1 in DLBCL tumor tissues. Knockdown of NFS1 decreased the cell viability and enhanced LDH levels in DLBCL cells. Animal experiments further indicated that downregulation of NFS1 suppresses tumor growth in vivo. NFS1 knockdown increased the lipid reactive oxygen species (ROS) level in cells, and this promotional effect was reversed by ferroptosis inhibitors, but not influenced by other types of cell death inhibitors. This result suggested that NFS1 depletion-impaired cell viability is associated with ferroptosis. Silenced NFS1 aggravated ferroptosis inducers caused cell viability inhibition, lactate dehydrogenase (LDH), and lipid ROS levels enhancement, while the addition of ferroptosis inhibitors abated these trends. Moreover, catalytic residue mutation of NFS1 did not affect its protein expression but decreased the cell viability, which was promoted by NFS1 upregulation, indicating that the protective effect of NFS1 in DLBCL cells was related to its catalytic activity. Further results showed that frataxin (FXN), the upstream activator of NFS1, reduced the cell viability in NFS1 upregulated cells. Consistent with NFS1, FXN silencing aggravated erastin-induced cell viability inhibition and LDH level enhancement. Silencing NFS1 or FXN inhibited the level of iron ions storage-related proteins but promoted the level of transport-related proteins. In addition, silenced NFS1 or FXN displayed an inhibition effect on protein expression of DNA polymerases, but a promotion trend in the phosphorylation of DNA damage markers. In conclusion, we demonstrated that ISC-related proteins NFS1 and FXN protect DLBCL cells from ferroptosis and DNA damage, thus exhibiting an essential role in DLBCL progression.
研究领域:
肿瘤学
·
分子生物学
·
血液病学
·
细胞生物学
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氧化应激
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF COLLOID AND INTERFACE SCIENCE
·
2025
·
IF 9.7
Guanhong Liu,Rongze Tang,Congcong Wang,Dehong Yu,Zhenxin Wang,Haochen Yang,Jia Wei,Shunhua Zhu,Fenglei Gao,Feng Yuan,Bin Pan
Cuproptosis and ferroptosis are difficult to synergize in tumor suppression due to their spatiotemporal asynchrony and mechanistic dispersion. Therefore, we proposed a new paradigm of Ferroptosis-Cuproptosis self-recycling. An iron‑sulfur cluster (Fe-S) metabolic collapse was constructed by hyaluronic acid (HA)-functionalized bimetallic nano-enzymes (HA@CuCo-NC) to initiate this tumoricidal mechanism. HA@CuCo-NC specifically accumulates in osteosarcoma cells through HA-mediated targeting. The multi-enzyme activity triggers a surge of reactive oxygen species (ROS) in the tumor microenvironment, which, along with Co 2+ , induces ferroptosis. This leads to severe mitochondrial damage and glutathione (GSH) depletion, which in turn activates the cuproptosis cascade. Cuproptosis causes Fe-S protein degradation and Fe 2+ release into the labile iron pool (LIP) by inhibiting Fe-S cluster formation and dihydrolipoamide acetyltransferase (DLAT) oligomerization. The released Fe 2+ enhances oxidative stress and promotes membrane disassembly via the Fenton reaction. The two act synergistically to form a dynamic self-reinforcing cycle: Ferroptosis-related mitochondrial damage exacerbates the toxicity of Cu 2+ . Cuproptosis-released Fe 2+ further activates ferroptosis. In vivo experiments demonstrated that HA@CuCo-NC significantly inhibited the growth of osteosarcoma in situ without causing systemic toxicity. This research introduces a novel approach to treating solid tumors by reconstructing the metabolic interaction network of copper and iron.
研究领域:
肿瘤学
·
纳米医学
·
分子生物学
·
细胞死亡机制
·
金属代谢
·
转化医学
·
氧化应激
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF CONTROLLED RELEASE
·
2025
·
IF 11.5
Enze Li,Liewei Wen,Caiyun Yin,Nan Wang,Suleixin Yang,Wenzheng Feng,Meiwan Chen
Cuproptosis as a copper-dependent cell death modality driven by pathological aggregation of lipoylated proteins and proteotoxic stress resulting from destabilization of iron-sulfur (Fe S) cluster proteins, represents a promising therapeutic strategy for cancer. However, the therapeutic efficacy of cuproptosis can be compromised by the intrinsic compensatory mechanisms within cancers, particularly low intracellular copper ion concentration and protective autophagy, which facilitates cellular adaptation and survival under stress. To overcome this limitation, a self-amplifying cuproptosis nanoregulator (SHK-Cu/ TK PF/pATG5@HA, abbreviated as SC/TpA@HA) for CD44-targeted delivery is developed that integrate shikonin‑copper (SHK-Cu) coordination complexes with CRISPR/Cas9 plasmids targeting ATG5, condensed by fluorinated polyethyleneimine ( TK PF)-condensed to enhance cancer therapy. Briefly, Cu + is released from the dissociated SHK-Cu complex upon intracellular GSH activation induces dihydrolipoamide S -acetyltransferase (DLAT) oligomerization and reduces Fe S cluster proteins, triggering tricarboxylic acid (TCA) cycle collapse and irreversible mitochondrial damage. Concurrently, CRISPR/Cas9-mediated ATG5 knockout prevents autophagosome formation, creating an autophagic flux trap that accumulates copper-damaged mitochondria. Notably, such mitochondrial dysfunction as induced by copper overload combined with impaired cellular damage clearance from autophagy blockade elevates cuproptosis. In addition, the immunogenic cell death through cuproptosis in cancer cells, as validated by the exposure of calreticulin and the extracellular release of HMGB1, triggers a potent anti-tumor immune response. This response is enhanced through autophagy inhibition, as ATG5 deletion blocks the downstream signaling of copper-activated Unc-51-like autophagy activating kinase 1/2 (ULK1/2), ultimately amplifying cytotoxic T lymphocyte infiltration. Therefore, this dual intervention through copper overload and autophagy blockade potentiates both cuproptosis and anti-tumor immune effect, representing an innovative strategy of cuproptosis treatment.
研究领域:
肿瘤学
·
分子生物学
·
纳米医学
·
免疫学
·
细胞死亡机制
·
基因编辑
·
代谢调控
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转化医学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Nano Today
·
2024
·
IF 13.2
Shiwen Duan,Jianmin Gao,Haoqin Ke,Chengquan Huang,Chaoyue Sun,Yujie Ren,Yixue Zhang,Xiumei Jiang,Yinliang Wang,Gang Liu
Mosquitoes are notorious for transmitting arbovirus diseases. Existing genetic-based control strategies only target one of mosquitoes’ flying, blood-sucking and reproduction behaviors and are technically demanding, limiting their real-world application. Therefore, there is an imperative need to identify novel molecular targets for developing multi-effect, easy-to-deploy mosquito control strategies. We herein identified and characterized the function of mosquito iron-sulfur-cluster assembly protein AalbNFS1. Silencing AalbNFS1 with double-strand RNAs (dsNFS1) caused evident metabolic and enzyme activity abnormalities in mosquito tissues and cells. Further analyses revealed that AalbNFS1 deficiency simultaneously reduced mosquitoes’ flying, blood-sucking and reproductive abilities by inducing muscle cell ferroptosis, confirming AalbNFS1 as a multi-effect molecular target for mosquito control purposes. To facilitate the real-world deployment of dsNFS1, a chitosan-tripolyphosphate-dsNFS1 (CS-TPP-dsNFS1) nanosystem was synthesized, generating satisfactory mosquito control effects. Collectively, our study pioneers the research on iron-sulfur-cluster biosynthesis mechanisms in mosquitoes and develops an effective mosquito control nanosystem with promising real-world applicability.
研究领域:
昆虫学
·
分子生物学
·
生物技术
·
公共卫生
✓ 已验证
产品关联
DOI
高影响因子
Antioxidants
·
2024
·Vol. 13
·期 9
·1036
·
IF 6
Lin Wu,Fei Huang,Zichen Sun,Jinghua Zhang,Siyu Xia,Hongting Zhao,Yutong Liu,Lu Yang,Yibing Ding,Dezhi Bian,Kuanyu Li,Yu Sun
Background: Diabetic peripheral neuropathy (DPN) is considered one of the most common chronic complications of diabetes. Impairment of mitochondrial function is regarded as one of the causes. Iron–sulfur clusters are essential cofactors for numerous iron–sulfur (Fe-S)-containing proteins/enzymes, including mitochondrial electron transport chain complex I, II, and III and aconitase. Methods: To determine the impact of hyperglycemia on peripheral nerves, we used Schwann-like RSC96 cells and classical db/db mice to detect the expression of Fe-S-related proteins, mitochondrially enzymatic activities, and iron metabolism. Subsequently, we treated high-glucose-induced RSC96 cells and db/db mice with pioglitazone (PGZ), respectively, to evaluate the effects on Fe-S cluster biogenesis, mitochondrial function, and animal behavior. Results: We found that the core components of Fe-S biogenesis machinery, such as frataxin (Fxn) and scaffold protein IscU, significantly decreased in high-glucose-induced RSC96 cells and db/db mice, accompanied by compromised mitochondrial Fe-S-containing enzymatic activities, such as complex I and II and aconitase. Consequently, oxidative stress and inflammation increased. PGZ not only has antidiabetic effects but also increases the expression of Fxn and IscU to enhance mitochondrial function in RSC96 cells and db/db mice. Meanwhile, PGZ significantly alleviated sciatic nerve injury and improved peripheral neuronal behavior, accompanied by suppressed oxidative stress and inflammation in the sciatic nerve of the db/db mice. Conclusions: Iron–sulfur cluster deficiency may contribute to hyperglycemia-mediated DPN.
研究领域:
内分泌学
·
神经科学
·
药理学
·
细胞生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
·
2024
·
IF 2.5
Siyu Xia,Lin Wu,Jing Chen,Kuanyu Li,Dezhi Bian
Diabetes is one of the most prevalent metabolic disorders, and its incidence has been experiencing a steady annual rise in recent years. Diabetic peripheral neuropathy (DPN) represents the most frequent adverse complication, exerting a profound impact on the quality of life for those suffering from diabetes. The etiology of DPN is complex, including impaired mitochondrial function. Iron-sulfur clusters (Fe–S) are essential cofactors for numerous essential enzymes crucial for mitochondrial function. Our previous study showed that expression of Frataxin, encoded by the Fxn gene, is downregulated in leptin receptor knockout (so-called db/db) mice, a commonly used DPN mouse model. Fxn is one of the core components of Fe–S biogenesis machinery. Here, we found that the mitochondria-targeted antioxidant SS-31 markedly improved the behavioral indices and significantly mitigated the damage to the sciatic nerve. SS-31 treatment effectively elevated Fxn expression, meliorated mitochondrial function, and inflammation in the sciatic nerve (SCN). We also found that SS-31 effectively mitigated high glucose-induced disruption of iron and redox homeostasis in RSC96 cells, a typical cell model of DPN, thereby improving mitochondrial function. These findings suggest enhancing Fe–S biogenesis could be an effective therapeutic strategy for treating DPN.
研究领域:
代谢性疾病
·
神经科学
·
分子生物学
·
糖尿病研究
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产品关联
DOI
PubMed
高影响因子
Scientific Reports
·
2018
·Vol. 8
·期 1
·1-11
·
IF 4.122
Li Huihui,Zhao Hongting,Hao Shuangying,Shang Longcheng,Wu Jing,Song Chuanhui,Meyron-Holtz Esther G.,Qiao Tong,Li Kuanyu
Iron is essential for growth and proliferation of mammalian cells. The maintenance of cellular iron homeostasis is regulated by iron regulatory proteins (IRPs) through binding to the cognate iron-responsive elements in target mRNAs and thereby regulating the expression of target genes. Irp1 or Irp2 -null mutation is known to reduce the cellular iron level by decreasing transferrin receptor 1 and increasing ferritin. Here, we report that Irp1 or Irp2 -null mutation also causes downregulation of frataxin and IscU, two of the core components in the iron-sulfur cluster biogenesis machinery. Interestingly, while the activities of some of iron-sulfur cluster-containing enzymes including mitochondrial aconitase and cytosolic xanthine oxidase were not affected by the mutations, the activities of respiratory chain complexes were drastically diminished resulting in mitochondrial dysfunction. Overexpression of human ISCU and frataxin in Irp1 or Irp2 -null cells was able to rescue the defects in iron-sulfur cluster biogenesis and mitochondrial quality. Our results strongly suggest that iron regulatory proteins regulate the part of iron sulfur cluster biogenesis tailored specifically for mitochondrial electron transport chain complexes.
研究领域:
分子生物学
·
细胞生物学
·
生物化学
✓ 已验证
DOI
PubMed
高影响因子
ADVANCED FUNCTIONAL MATERIALS
·
2023
·
IF 19
Fan Zhao,Liying Liang,Heng Wang,Chen Wang,Dan Su,Yao Ying,Wangchang Li,Juan Li,Jingwu Zheng,Liang Qiao,Xiaozhou Mou,Shenglei Che,Jing Yu
Copper overload is a novel way to achieve copper-ion-interference therapy by disrupting copper homeostasis and treating diseases through multiple cell death pathways. However, it is difficult to reach copper overload since excess intracellular copper ions will be pumped out. Herein, copper overload is achieved by both raising cellular uptake and reducing the efflux of copper ions using hydrogen sulfide (H 2 S)-responsive copper hydroxyphosphate nanoparticles (Cu 2 (PO 4 )(OH) NPs). After immersion in an H 2 S-enriched colon cancer microenvironment, Cu 2 (PO 4 )(OH) NPs can transform into copper sulfide NPs with reduced size for higher cell entering, resulting in improved Fenton activity as well as copper ion dissociation. Reactive oxygen species generated by the Fenton reaction not only activate inflammasomes and Caspase-1 proteins, cause the cleavage of gasdermin D to induce pyroptosis, but also affect mitochondrial function and down-regulate copper exporter ATP7A to further reduce the copper excretion. The combination of higher endocytosis and lower exportation leads to maximized copper overload. Together with the efficient copper ions release, mitochondrial tricarboxylic acid cycle can be disrupted and iron-sulfur cluster proteins are downregulated, ultimately triggering cuproptosis. As both pyroptosis and cuproptosis are efficient ways to induce cell death, this study provides a novel way to realize effective tumor-targeted therapy based on H 2 S-activated copper overload with simple Cu 2 (PO 4 )(OH) NPs.
研究领域:
肿瘤学
·
纳米技术
·
细胞生物学
·
治疗学
✓ 已验证
产品关联
DOI
高影响因子
Scientific Reports
·
2017
·Vol. 7
·期 1
·1-11
·
IF 4.259
Zhao Hongting,Li Huihui,Hao Shuangying,Chen Jiping,Wu Jing,Song Chuanhui,Zhang Meng,Qiao Tong,Li Kuanyu
Friedreich ataxia is a progressive neurodegenerative disease caused by the expansion of GAA trinucleotide repeats within the first intron of the FXN gene, which encodes frataxin. The pathophysiology of the disease is thought to be derived from the decrease of Fe-S cluster biogenesis due to frataxin deficiency. There is currently no effective treatment for the disease. In our study, we demonstrated that treatment with the mitochondrion-targeted peptide SS-31 reduced frataxin deficiency-induced oxidative stress in lymphoblasts and fibroblasts derived from patients. Interestingly, SS-31 treatment translationally upregulated the protein level of frataxin in a dose-dependent manner. Furthermore, SS-31 treatment increased the enzymatic activities of the iron-sulphur enzymes, including aconitase and complex II and III of the respiratory chain. Further evaluation of the quality of mitochondria showed that mitochondrial membrane potential, ATP content, NAD + /NADH, and the morphology of mitochondria all improved. Our results suggest that SS-31 might potentially be a new drug for the early treatment of Friedreich ataxia.
研究领域:
神经退行性疾病
·
分子生物学
·
线粒体生物学
·
遗传病
✓ 已验证
DOI
PubMed
高影响因子
Frontiers in Pharmacology
·
2024
·
IF 4.4
Peng Min,Zhang Chen,Duan Yuan-Yuan,Liu Hai-Bo,Peng Xin-Yuan,Wei Qian,Chen Qi-Ying,Sang Hong,Kong Qing-Tao
Fungal infections have become clinically challenging owing to the emergence of drug resistance in invasive fungi and the rapid increase in the number of novel pathogens. The development of drug resistance further restricts the use of antifungal agents. Therefore, there is an urgent need to identify alternative treatments for Cryptococcus neoformans (C. neoformans). Disulfiram (DSF) has a good human safety profile and promising applications as an antiviral, antifungal, antiparasitic, and anticancer agent. However, the effect of DSF on Cryptococcus is yet to be thoroughly investigated. This study investigated the antifungal effects and the mechanism of action of DSF against C. neoformans to provide a new theoretical foundation for the treatment of Cryptococcal infections. In vitro studies demonstrated that DSF inhibited Cryptococcus growth at minimum inhibitory concentrations (MICs) ranging from 1.0 to 8.0 μg/mL. Combined antifungal effects have been observed for DSF with 5-fluorocytosine, amphotericin B, terbinafine, or ketoconazole. DSF exerts significant protective effects and synergistic effects combined with 5-FU for Galleria mellonella infected with C. neoformans. Mechanistic investigations showed that DSF dose-dependently inhibited melanin, urease, acetaldehyde dehydrogenase, capsule and biofilm viability of C. neoformans. Further studies indicated that DSF affected C. neoformans by interfering with multiple biological pathways, including replication, metabolism, membrane transport, and biological enzyme activity. Potentially essential targets of these pathways include acetaldehyde dehydrogenase, catalase, ATP-binding cassette transporter (ABC transporter), and iron-sulfur cluster transporter. These findings provide novel insights into the application of DSF and contribute to the understanding of its mechanisms of action in C. neoformans.
研究领域:
药理学
·
微生物学
·
传染病学
·
真菌学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
CHEMICAL ENGINEERING JOURNAL
·
2024
·
IF 13.3
Fan Zhao,Hongyan Yu,Chen Wang,Junchen Xu,Hao Gao,Yao Ying,Wangchang Li,Juan Li,Jingwu Zheng,Liang Qiao,Shenglei Che,Jing Yu
Cuproptosis, ferroptosis, and reactive oxygen species (ROS)-involved apoptosis are all bound by the overexpressed glutathione (GSH) in tumor microenvironment (TME). Herein, a dual GSH depletor is developed based on copper/iron bimetal gallic acid phenolic networks (CuFeGA MPNs) for combination tumor therapy by GSH depletion boosted apoptosis/ferroptosis/cuproptosis simultaneously. The CuFeGA MPNs are dissociated following exposure to the highly expressed GSH, causing the release of large quantities of GA, Fe 2+ , and Cu + . The released GA then further consumes the residual GSH. In conjunction with the GSH response-consumption behavior, the GSH depletion is achieved by those dual GSH consumption procedures. Subsequently, the expression of glutathione peroxides 4 (GPX4) is down-regulated by GSH depletion for further accumulation of lipid peroxides (LPO). Moreover, intracellular ROS levels are improved via Fenton reaction with released Cu + and Fe 2+ , leading to buildup of LPO concurrently. Eventually, excess ROS can activate mitochondria-associated apoptosis, and the surge of LPO initiates ferroptosis without GSH homeostasis. Meanwhile, the oligomerization of lipoylated dihydrolipoamide S-acetyltransferase (DLAT) and decline of iron-sulfur cluster protein are induced by excessive Cu + in the absence of GSH chelation, activating cuproptosis. This work provides a feasible approach for the realization of multiple mechanisms combined tumor therapy.
研究领域:
癌症生物学
·
材料科学
·
纳米技术
·
生物化学
·
治疗学
✓ 已验证
产品关联
DOI
高影响因子
Advanced Healthcare Materials
·
2023
·
IF 10
Fan Zhao,Hongyan Yu,Liying Liang,Chen Wang,Dier Shi,Xiangyu Zhang,Yao Ying,Wei Cai,Wangchang Li,Juan Li,Jingwu Zheng,Liang Qiao,Shenglei Che,Jing Yu
The combination of chemo/chemodynamic therapy is a promising strategy for improving antitumor efficacy. Herein, metal-phenolic network nanoparticles (NPs) self-assembled from copper ions and gallic acid (Cu-GA) are developed to evoke apoptosis and cuproptosis for synergistic chemo/chemodynamic therapy. The Cu-GA NPs are biodegraded in response to the highly expressed glutathione (GSH) in tumor cells, resulting in the simultaneous release of Cu + and GA. The intracellular GSH content is dramatically reduced by the released GA, rendering the tumor cells incapable of scavenging reactive oxygen species (ROS) and more susceptible to cuproptosis. Meanwhile, ROS levels within the tumor cells are significantly increased by the Fenton-like reaction of released Cu + , which disrupts redox homeostasis and achieves apoptosis-related chemodynamic therapy. Moreover, massive accumulation of Cu + in the tumor cells further induces aggregation of lipoylated dihydrolipoamide S-acetyltransferase and downregulation of iron-sulfur cluster protein, activating cuproptosis to enhance the antitumor efficacy of Cu-GA NPs. The experiments in vivo further demonstrate that Cu-GA NPs exhibited the excellent biosafety and superior antitumor capacity, which can efficiently inhibit the growth of tumors due to the activation by the tumor specific GSH and hydrogen peroxide. These Cu-based metal-phenolic network NPs provide a potential strategy to build up efficient and safe cancer therapy.
研究领域:
纳米技术
·
癌症治疗
·
生物化学
·
药理学
·
材料科学
✓ 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）