TOXICOLOGY
·
2020
·
IF 4.099
Yuwei Yang,Jing Chen,Qin Gao,Xin Shan,Jie Wang,Zhiyang Lv
Ginkgolide B (GB), a main constituent of Ginkgo biloba extracts, reduces hepatic lipid accumulation and ameliorates nonalcoholic fatty liver disease (NAFLD) in obese mice, but the potential mechanism is unclear. Here we investigated the attenuated effects of GB on the disorder of lipid metabolism, oxidative stress and iron deposition in NAFLD and its potential mechanism associated with ferroptosis. Our preliminary research focused on high fat diet (HFD)-induced ApoE −/− mice gavaged with GB (20 and 30 mg kg -1 •d -1 , approximately equal to the human dose of 2 and 3 mg kg -1 •d -1 , respectively) and palmitic acid and oleic acid (PA/OA)-induced HepG2 cells treated with GB (4, 8, 16 μg/mL), respectively. Hepatic injury was assessed via biochemical, histopathological and immunohistochemical evaluations. In order to examine the mechanism of GB on ferroptosis-regulated pathway, we analyzed the expression levels of ferroptosis-related proteins, including nuclear factor erythroid 2 (Nrf2), glutathione peroxidase 4 (GPX4), heme oxygenase-1 (HO-1), transferrin receptor-1 (TFR1) and ferritin heavy chain-1 (FTH1) in vivo and vitro experiments by Western blotting. In order to further verify the correlation pathway of ferroptosis, after Nrf2 short hairpin RNA interference, we analyzed the effects of GB on Nrf2 pathway. Both HFD-fed mice and PA/OA-induced HepG2 cells displayed ferroptosis-based panel of biomarkers such as iron overload with the up-regulation of TFR1 and the down-regulation of FTH1, lipid peroxidation and inhibition of Nrf2 activity, which further induced GPX4 and HO-1 levels. Remarkably, after Nrf2 interference, GB treatment significantly increased Nrf2 expression, indicating that GB exerted anti-ferroptosis effects by activation of Nrf2 pathway. Our results are preliminarily illustrated that GB treatment has a specific effect on lipid accumulation and oxidative stress caused ferroptosis in NAFLD, possibly through Nrf2 signaling pathway.
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DRUG DELIVERY
·
2025
·
IF 8.1
Jinguo Li,Yuhao Zhang,Changyu Shao,Yining Bai,Puxiu Wang,Tianyang Ren
Triple-negative breast cancer (TNBC) is the most aggressive type of breast cancer and is characterized by high invasiveness, rapid recurrence, and poor prognosis. To date, the ferroptosis-combined therapies have exerted their potential in the TNBC treatments via multi-mechanisms. Here, we reported a doxorubicin (DOX)–Fe complex and RSL3 co-loaded liposomes (DOX–Fe/RSL3@LIPs) for ferroptosis-enhanced chemotherapy on TNBC tumors. This nanoformulation performed a uniform spherical structure with a mean particle size of 126.9 nm, a zeta potential of −3.56 mV, and high colloidal stability. The pH-responsive dissociation of DOX–Fe and release of DOX were conducive to drug accumulation in the tumor microenvironment and tumor cells, meanwhile efficiently suppressed free DOX leakage in the blood circulation, potentially reducing the cardiotoxicity of DOX. In vitro cell and in vivo pharmacodynamic studies demonstrated a favorable anticancer effect of the DOX–Fe/RSL3@LIPs on 4T1 tumors by synchronously delivering biologically active DOX, Fe2+, and RSL3 to the tumor sites. DOX induced tumor cell death through a dual pathway of apoptosis/ferroptosis, and promoted the H2O2 generation. The tumor cell ferroptosis was observably enhanced via supplements of the ferrous ions and H2O2, and RSL3-derived GPX4 inhibition to severely destroy the oxidation balance in cells. In this paper, the DOX–Fe/RSL3@LIPs have exerted a synergistic anticancer effect on TNBC by combining ferroptosis and conventional chemotherapy, and made a meaningful exploration of new strategies for TNBC therapy.
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JOURNAL OF HAZARDOUS MATERIALS
·
2021
·
IF 10.588
Yuhao Wu,Junke Wang,Tianxin Zhao,Jiadong Chen,Lian Kang,Yuexin Wei,Lindong Han,Lianju Shen,Chunlan Long,Shengde Wu,Guanghui Wei
Di-(2-ethylhexyl) phthalate (DEHP) is an extensively used plasticizer and has been shown to cause reproductive dysfunction in humans and model animals. However, the exact mechanisms of testicular injury induced by DEHP exposure have not been fully clarified. Using gas chromatography-mass spectrometry, we found that mono-2-ethylhexyl ester (MEHP, a major biometabolite of DEHP) and DEHP concentrations were elevated in mouse serum after DEHP exposure. Using RNA-seq, we found that ferroptosis and HIF-1 signaling pathways might be involved in testicular injury due to prepubertal DEHP exposure. Subsequent Western blotting, ferrous iron and MDA measurements, and immunofluorescence of testicular sections verified the RNA-seq findings. Consistently, based on the RNA-seq findings, we found that ferroptosis and HIF-1 signaling pathways might play crucial roles in Leydig and Sertoli cell injury due to MEHP exposure in vitro. Further experiments also confirmed ferroptosis in Leydig and Sertoli cells. Using Western blotting, cellular immunofluorescence and ChIP-qPCR, we found that MEHP exposure caused HIF-1α accumulation and stabilization, resulted in HIF-1α translocation into the nucleus, and induced HIF-1α/ Hmox1 binding in Leydig and Sertoli cells. To clarify whether HIF-1α plays a pivotal role in MEHP-induced ferroptosis, we knocked out Hif-1α using the CRISPR/Cas9 technique. We found that Hif-1α knockout rescued MEHP-induced ferroptosis. In summary, our findings certified that prepubertal DEHP exposure led to ferroptosis in mouse testes via the HIF-1α/HO-1 signaling pathway.
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Exploration
·
2024
·
IF 0
Xue Bai,Jun Kang,Silong Wei,Yun Wang,Yangsui Liu,Bo Yuan,Qian Lu,Huansong Li,Jun Yan,Xi Yang,Jin Chang
Sonodynamic therapy offers a non-invasive approach to induce the death of tumor cells. By harnessing ultrasound waves in tandem with sonosensitizers, this method produces reactive oxygen species (ROS) that inflict oxidative damage upon tumor cells, subsequently causing their demise. Ferroptosis is a regulatory form of cell death that differs from other forms, characterized by iron accumulation, ROS accumulation, and lipid peroxidation. In the presented research, a nanoparticle formulation, parthenolide/ICG-CaCO 3 @lipid (PTL/ICG-CaCO 3 @Lip), has been engineered to amplify ferroptosis in tumor cells, positioning it as a potent agent for sonodynamic cancer immunotherapy. This nanoparticle significantly augments ROS levels within tumor cells, inducing oxidative stress that leads to cell death. The therapeutic potential of PTL/ICG-CaCO 3 @Lip, both in vivo and in vitro, has been convincingly demonstrated. Furthermore, RNA-seq analysis insights revealed that PTL/ICG-CaCO 3 @Lip facilitates tumor cell ferroptosis by regulating P53 to downregulate SLC7A11 protein expression, thereby inhibiting the glutamate-cystine antiporter system Xc − and stimulating ACSL4/LPCAT3 pathways. This pioneering work uncovers an innovative strategy for combatting tumors, leveraging enhanced oxidative stress to promote cell ferroptosis, and paves the way for groundbreaking cancer immunotherapeutic interventions.
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MedComm
·
2024
·Vol. 5
·期 12
·e70033
·
IF 10.7
Jing Li,Mimi Chen,Dingwen Huang,Ziyin Li,Yu Chen,Jinhua Huang,Yuanqun Chen,Zhili Zhou,Zhiying Yu
Ovarian cancer (OV) ranks among the deadliest gynecological cancer, known for its high risk of relapse and metastasis, and a general resistance to conventional platinum‐based chemotherapy. Selenoprotein I (SELENOI) is a crucial mediator implicated in human hereditary spastic paraplegia. However, its role in human tumors remains poorly elucidated. Here, we comprehensively analyzed SELENOI expression patterns, functions, and clinical implications across various malignancies through the integration of bulk transcriptomics, cancer databases, and in vitro and in vivo experiments. Pan‐cancer analysis indicated upregulated SELENOI expression across various cancers, correlating with augmented malignancy, suppressed tumor immunity and poor prognosis. Knockdown of SELENOI caused G0/G1‐phase cell cycle arrest and diminished aggressive cancer phenotypes in OV cells. Moreover, SELENOI inhibition augments ferroptosis and reverses the cisplatin resistance in OV cells by modulating Akt phosphorylation. Conversely, overexpression of SELENOI in OV cells enhanced therapeutic sensitivity to cisplatin by upregulating Akt phosphorylation. Importantly, in vivo studies demonstrated that SELENOI inhibition suppressed ovarian tumor growth and enhanced cisplatin's anticancer effects. These findings highlight the significant role of SELENOI in OV by modulating ferroptosis and chemotherapy resistance. Targeting SELENOI represents a promising therapeutic approach to promote the efficacy of platinum‐based chemotherapy in OV, particularly in cases of resistance. Graphic summary of targeting SELENOI for promoting ferroptosis and reversing chemoresistance in ovarian cancer. Inhibition of SELENOI activated unsaturated fatty acid synthesis and impaired Akt phosphorylation, resulting in the upregulation of ACSL4 expression and induction of ferroptosis. Reduced Akt phosphorylation also led to the downregulation of ALDH3A1 expression, a key gene associated with cisplatin‐resistance, thereby enhancing cisplatin cytotoxicity in SELENOI‐silenced ovarian cancer cells.
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JOURNAL OF NANOBIOTECHNOLOGY
·
2026
·
IF 15
Huang Zhangrui,Yin Feiying,Tan Ying,Huang Yuqi,Li Tianjie,Ma Chuwen,Pang Zhiquan,Zhang Rongwei,Zhao Xin,Su Yongfeng,Zheng Li,Zhong Jingping,Liu Jianwei
Aberrant endoplasmic reticulum (ER)–mitochondria crosstalk at mitochondria-associated ER membranes (MAMs) drives oxidative stress, calcium dysregulation, pyroptosis, and ferroptosis in nucleus pulposus cells, accelerating intervertebral disc degeneration (IVDD). Nanozymes that mimic antioxidant enzymes and remodel the oxidative stress microenvironment are promising for IVDD treatment, but their efficacy is limited by low enzyme-like activity and poor targeting of MAMs. To address this, we developed a space-confined pyrolysis strategy to synthesize N/O co-doped hollow bamboo-like porous carbon nanotubes loaded with atomically Janus MnSe dual atoms, and functionalization with the MAM-targeting protein GRP75 and σ1R-regulator CGI1746 yielded GC-MnSe DA /BCNT, an integrated nanozyme platform for precise IVDD intervention. The hollow BCNT framework exposed atomically dispersed MnSe sites, while the MnSeN 5 O Janus active center optimizes Mn’s local electronic structure via Se-mediated p-d orbital hybridization, promoting electron transfer and lowering the reaction energy barrier, thereby boosting SOD-, CAT-, and GPx-like activities. This platform exhibited high biosafety and potent multi-enzyme antioxidant activity, enabling efficient ROS scavenging and inhibition of lipid peroxidation. Importantly, it restored the integrity of MAMs and mitochondrial function, maintained Ca 2 ⁺ homeostasis, and suppressed NLRP3-mediated pyroptosis and ferroptosis, thereby delaying IVDD progression. This work provides an efficient, safe, and precise new strategy for the treatment of degenerative and inflammatory diseases. Graphical abstract
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高影响因子
CELLULAR SIGNALLING
·
2026
·
IF 4.7
Chunju Yang,Hanfeng Hu,Yang Yang,Pengrui Jing,Shaofeng Yang,Jiangbo Guo,Li Chu,Hao Ni,Bin Meng,Shuli Yang,Fanqi Kong,Jinhui Shi
Intervertebral disc degeneration (IVDD) is the leading cause of low back pain, affecting 619 million people worldwide in 2020, yet no effective disease-modifying therapy is clinically available to reverse its progression. Ferroptosis has been proven to be a core driver of IVDD by inducing injury to nucleus pulposus cells (NPCs). The regulatory role of cystathionine β-synthase (CBS) in IVDD and its underlying molecular mechanisms remain unclear. This study aimed to investigate the biological function of CBS in IVDD and elucidate the mechanism by which it regulates NPC ferroptosis. We found that CBS expression was significantly downregulated in degenerated human NP tissues and rat IVDD models and was negatively correlated with degeneration severity and ferroptosis activation. Functional assays showed that CBS knockdown markedly exacerbated TBHP-induced matrix metabolic imbalance, senescence, and ferroptosis in NPCs, while CBS overexpression effectively alleviated these pathological phenotypes. Transcriptomic analysis, biochemical validation, and pharmacological inhibition experiments implicated PI3K-AKT signaling in the ferroptosis-related effects associated with CBS modulation in NPCs. In vivo, S-Adenosyl-L-methionine (SAM) administration attenuated needle puncture-induced IVDD in rats, restored disc height and NP water content, and suppressed intradiscal ferroptosis. Because SAM has pleiotropic biological actions, these in vivo effects cannot be attributed exclusively to CBS. Collectively, our findings support a protective role for CBS against IVDD through suppression of NPC ferroptosis and implicate PI3K-AKT signaling as a contributing pathway.
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高影响因子
ACS Applied Materials & Interfaces
·
2024
·
IF 8.3
Wenyan Hao,Nan Sun,Yueyue Fan,Mengyu Chen,Qianqian Liu,Meiyan Yang,Yang Yang,Chunsheng Gao
Ferroptosis therapy and immunotherapy have been widely used in cancer treatment. However, nonselective induction of ferroptosis in tumors is prone to immunosuppression, limiting the therapeutic effect of ferroptosis cancer treatment. To address this issue, this study reports a customized hybrid nanovesicle composed of NK cell-derived extracellular versicles and RSL3-loaded liposomes (hNRVs), aiming to establish a positive cycle between ferroptosis therapy and immunotherapy. Thanks to the enhanced permeability and retention effect and the tumor homing characteristics of NK exosomes, our data indicate that hNRVs can actively accumulate in tumors and enhance cellular uptake. FASL, IFN-γ, and RSL3 are released into the tumor microenvironment, where FASL derived from NK cells effectively lyses tumor cells. RSL3 downregulates the expression of GPX4 in the tumor, leading to the accumulation of LPO and ROS, and promotes ferroptosis in tumor cells. The accumulation of IFN-γ and TNF-α stimulates the maturation of dendritic cells and effectively induces the inactivation of GPX4, promoting lipid peroxidation, making them sensitive to ferroptosis and indirectly promoting the occurrence of ferroptosis. This study highlights the role of the customized hNRV platform in enhancing the effectiveness of synergistic treatment with selective delivery of ferroptosis inducers and immune activation against glioma without causing additional side effects on healthy organs.
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高影响因子
Advanced Science
·
2021
·Vol. 8
·期 10
·2004680
·
IF 16.806
Jingyi Guo,Lifan Duan,Xueying He,Shengbiao Li,Yi Wu,Ge Xiang,Feixiang Bao,Liang Yang,Hongyan Shi,Mi Gao,Lingjun Zheng,Huili Hu,Xingguo Liu
Mitochondrial DNA depletion syndrome (MDS) is a group of severe inherited disorders caused by mutations in genes, such as deoxyribonucleoside kinase (DGUOK). A great majority of DGUOK mutant MDS patients develop iron overload progressing to severe liver failure. However, the pathological mechanisms connecting iron overload and hepatic damage remains uncovered. Here, two patients’ skin fibroblasts are reprogrammed to induced pluripotent stem cells (iPSCs) and then corrected by CRISPR/Cas9. Patient-specific iPSCs and corrected iPSCs-derived high purity hepatocyte organoids (iHep-Orgs) and hepatocyte-like cells (iHep) are generated as cellular models for studying hepatic pathology. DGUOK mutant iHep and iHep-Orgs, but not control and corrected one, are more sensitive to iron overload-induced ferroptosis, which can be rescued by N-Acetylcysteine (NAC). Mechanically, this ferroptosis is a process mediated by nuclear receptor co-activator 4 (NCOA4)-dependent degradation of ferritin in lysosome and cellular labile iron release. This study reveals the underlying pathological mechanisms and the viable therapeutic strategies of this syndrome, and is the first pure iHep-Orgs model in hereditary liver diseases.
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CNS Neuroscience & Therapeutics
·
2025
·Vol. 31
·期 2
·e70238
·
IF 5
Shihao Chen,Linqian Zhao,Xing Jin,Qichang Liu,Yuqing Xiao,Huiqin Xu
The AST activates the Nrf2/GPX4 signaling pathway to regulate glutathione metabolism and inhibit ferroptosis to preventing epileptic seizures.
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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.
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JOURNAL OF ETHNOPHARMACOLOGY
·
2025
·
IF 5.4
Nana Gao,Zongyu Huang,Jianjie Xie,Shuang Gao,Biaobiao Wang,Huicong Feng,Cuifen Bao,He Tian,Xia Liu
Ethnopharmacological relevance The Cryptotanshinone (CT) is a kind of Chinese medicine extracted from salvia miltiorrhiza, which has various pharmacological activities and is widely used in the treatment of diseases. Aim of the study The objective is to delve into the mechanism by which cryptotanshinone (CT) exerts its effects on rats with the middle cerebral artery occlusion/reperfusion (MCAO/R) model. Additionally, it aims to further assess the interplay between inflammation and oxidative stress, along with the underlying mechanism of CT's anti-ferroptosis function. Materials and methods We constructed the middle cerebral artery occlusion/reperfusion (MCAO/R) model in rats. The effects of cryptotanshinone (CT) were evaluated using 2,3,5 - triphenyltetrazolium chloride (TTC) staining, behavioral assays, immunofluorescence, hematoxylin - eosin (HE) staining, and Nissl staining. Additionally, in vitro, cell viability was assessed by the Cell Counting Kit - 8 (CCK - 8) assay following experimental dosing. Oxygen - glucose deprivation/oxidation (OGD/R) models were established in PC12 and BV2 cells. Flow cytometry was employed to detect cellular reactive oxygen species (ROS) expression. The activities of superoxide dismutase (SOD), malondialdehyde (MDA), glutathione peroxidase (GSH-px), andMitochondrial Membrane Potential Assay Kit with JC-1(JC-1) were measured using biochemical methods. Inflammatory factor levels were determined using enzyme-linked immunosorbent assay (ELISA) kits. Immunoblotting was used to detect the levels of rat phosphatidylinositol 3 - kinase (PI3K), phosphorylated-PI3K (P-PI3K), protein kinase B (AKT), phosphorylated - AKT (P-AKT), nuclear factor erythroid 2related factor 2 (Nrf2), solute carrier family 7 member 11 (SLC7A11), and glutathione peroxidase 4 (GPX4). Results In rats with the MCAO/R model, CT demonstrated the ability to decrease ROS levels, enhance the activity of glutathione (GSH), mitigate inflammation, augment the activity of glutathione peroxidase 4 (GPX4), inhibit ferroptosis, safeguard neurons, and facilitate the restoration of nerve function. Results from network pharmacology indicated that the action of CT might be mediated via the PI3K/Akt signaling pathway. Simultaneously, in-vivo investigations revealed that CT curbs ferroptosis through the PI3K/AKT/Nrf2 and SLC7A11/GPX4 signaling pathways. Conclusion CT can inhibit ferroptosis by inhibiting the vicious cycle between oxidative stress and inflammation, protect neurons and promote motor function recovery.
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