JOURNAL OF ETHNOPHARMACOLOGY
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2026
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IF 6.8
Zhengwang Guo,Huifeng Hao,Xinxin Deng,Yanna Jiao,Bin Dong,Dong Xue,Shu-Yan Han
Ethnopharmacological relevance Triple-negative breast cancer (TNBC) has a poor clinical prognosis and shows resistance to traditional treatments. Ferroptosis is a potential therapeutic strategy for TNBC. Although dandelion extract has demonstrated anti-tumor effects against TNBC, its role in regulating ferroptosis has not been elucidated. Aim of the study This study aimed to investigate the role and mechanisms of dandelion extract in inhibiting TNBC via the induction of ferroptosis. Materials and methods Cell viability and cell death were detected by CCK-8 assay and PI/Hoechst 33342 dual staining, respectively. Proteomic profiling was used to identify the mechanisms of dandelion extract-induced cell death. Ferroptosis was assessed by measuring key hallmarks, including Fe 2+ accumulation, lipid peroxidation, mitochondrial dysfunction, and ultrastructural changes. Mechanistic validation was achieved through target-specific interference and subsequent biomolecular analysis. Results Dandelion extract selectively induced cell death in TNBC cells without affecting normal MCF-10A cells. Proteomic and experimental evidence indicates that dandelion extract induces ferroptosis in TNBC cells, characterized by elevated Fe 2+ , ROS, lipid peroxidation, MDA levels, and mitochondrial dysfunction. Crucially, ferroptosis inhibitors attenuated the inhibitory effect of dandelion extract on TNBC cell viability, confirming ferroptosis as the primary cell death mechanism. Mechanistic studies have demonstrated that dandelion extract promoted ferroptosis in TNBC cells both in vitro and in vivo through NCOA4-mediated ferritinophagy. Conclusions This study demonstrates that dandelion extract induces ferroptosis in TNBC cells both in vitro and i n vivo by regulating ferritinophagy mediated by the NCOA4-FTH1 axis, thus suggesting novel therapeutic strategies for TNBC treatment.
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高影响因子
JOURNAL OF APPLIED TOXICOLOGY
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2023
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IF 3.3
Xiuli Liu,Guilan Li,Shaoxiong Chen,Huiyun Jin,Xiaodong Liu,Linfang Zhang,Zhaohui Zhang
Beryllium sulfate (BeSO 4 ) can result to lung injuries, such as leading to lipid peroxidation and autophagy, and the treatment of beryllium disease has not been well improved. Ferroptosis is a regulated cell death process driven by iron-dependent and lipid peroxidation, while ferritinophagy is a process mediated by nuclear receptor coactivator 4 (NCOA4), combined with ferritin heavy chain 1 (FTH1) degradation and release Fe 2+ , which regulated intracellular iron metabolism and ferroptosis. Hydrogen sulfide (H 2 S) has the effects of antioxidant, antiautophagy, and antiferroptosis. This study aimed to investigate the effect of H 2 S on BeSO 4 -induced ferroptosis and ferritinophagy in 16HBE cells and the underlying mechanism. In this study, BeSO 4 -induced 16HBE cell injury model was established based on cellular level and pretreated with deferoxamine (DFO, a ferroptosis inhibitor), sodium hydrosulfide (NaHS, a H 2 S donor), or NCOA4 siRNA and, subsequently, performed to detect the levels of lipid peroxidation and Fe 2+ and the biomarkers of ferroptosis and ferritinophagy. More importantly, our research found that DFO, NaHS, or NCOA4 siRNA alleviated BeSO 4 -induced ferroptosis and ferritinophagy by decreasing the accumulation of Fe 2+ and lipid peroxides. Furthermore, the relationship between ferroptosis, ferritinophagy, H 2 S, and beryllium disease is not well defined; therefore, our research is innovative. Overall, our results provided a new theoretical basis for the prevention and treatment of beryllium disease and suggested that the application of H 2 S, blocking ferroptosis, and ferritinophagy may be a potential therapeutic direction for the prevention and treatment of beryllium disease.
研究领域:
毒理学
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细胞生物学
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药理学
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肺科学
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高影响因子
Nutrients
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2022
·Vol. 14
·期 21
·4549
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IF 6.706
Tongtong Ba,Dai Zhao,Yiqin Chen,Cuiping Zeng,Cheng Zhang,Sai Niu,Hanchuan Dai
L-citrulline (L-cit) is a key intermediate in the urea cycle and is known to possess antioxidant and anti-inflammation characteristics. However, the role of L-cit in ameliorating oxidative damage and immune dysfunction against iron overload in the thymus remains unclear. This study explored the underlying mechanism of the antioxidant and anti-inflammation qualities of L-cit on iron overload induced in the thymus. We reported that L-cit administration could robustly alleviate thymus histological damage and reduce iron deposition, as evidenced by the elevation of the CD8+T lymphocyte number and antioxidative capacity. Moreover, the NF-κB pathway, NCOA4-mediated ferritinophagy, and ferroptosis were attenuated. We further demonstrated that L-cit supplementation significantly elevated the mTEC1 cells’ viability and reversed LDH activity, iron levels, and lipid peroxidation caused by FAC. Importantly, NCOA4 knockdown could reduce the intracellular cytoplasmic ROS, which probably relied on the Nfr2 activation. The results subsequently indicated that NCOA4-mediated ferritinophagy was required for ferroptosis by showing that NCOA4 knockdown reduced ferroptosis and lipid ROS, accompanied with mitochondrial membrane potential elevation. Intriguingly, L-cit treatment significantly inhibited the NF-κB pathway, which might depend on restraining ferritinophagy-mediated ferroptosis. Overall, this study indicated that L-cit might target ferritinophagy-mediated ferroptosis to exert antioxidant and anti-inflammation capacities, which could be a therapeutic strategy against iron overload-induced thymus oxidative damage and immune dysfunction.Keywords:L-citrulline;thymus;iron overload;ferritinophagy;ferroptosis
研究领域:
免疫学
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药理学
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细胞生物学
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生物化学
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高影响因子
CHEMICO-BIOLOGICAL INTERACTIONS
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2025
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IF 5.4
Yu Fu,Guiqin Huang,Yawen Cai,Menghui Ren,Run Cheng,Yuhui Chai,Yingdi Wang,Yunqi An,Tianhua Yan,Lingpeng Zhu,Xinxin Liu
Gastric cancer (GC) is a highly aggressive and heterogeneous malignancy. The process of ferroptosis regulates tumor growth and represents a promising therapeutic target for GCs. Despite Salidroside (Sal) being able to regulate ferroptosis in a variety of diseases, there are still limited reports on its therapeutic effects and potential targets in treating GC. This study aimed to investigate the potential mechanism of Sal-induced ferroptosis in GC. Our analysis, integrating databases like PharmMapper, Swiss Target Prediction, TargetNet, GeneCards, TTD, OMIM, STRING, and DAVID. Human gastric cancer MGC803 cells and tumor-bearing mice were used to evaluate the anti-tumor effect of Sal on GC in vitro and in vivo. CCK-8, LDH, and Calcein-AM/ PI were used to assess cell viability and damage. FerroOrange, Lillie’s Ferrous Iron Stain, MDA, ROS, BODIPY™ 581/591 C11, GSH, and GPxs were used to detect intracellular Fe 2+ concentration, lipid peroxidation level, and antioxidant defense system. qRT-PCR and western blot were performed to explore relevant mechanism studies. Network pharmacology results showed that Sal shares 322 targets with GC, which have biological functions related to lipid metabolism, cell death, and lipid peroxidation. Experiments further confirmed that Sal inhibits MGC803 cells by inducing ferroptosis, as evidenced by the induction of elevated Fe 2+ and increased lipid peroxidation. Fer-1, an inhibitor of ferroptosis, reversed the anti-GC effect of Sal in MGC803 cells and GC tumor-bearing mice. Further confirmation of the association between Sal and ferroptosis in GC. Subsequently, bioinformatics and machine learning algorithms identified nuclear receptor coactivator 4 (NCOA4) as a candidate signature gene associated with ferroptosis in GC, and molecular docking shows that NCOA4 binds Sal. We then performed in vivo and in vitro experiments to elucidate that Sal targeting NCOA4, a cargo receptor mediating ferritinophagy, mediates autophagic degradation of ferritin heavy chain 1 (FTH1, Fe 2+ storage protein), which further increases Fe 2+ and lipid peroxidation. In addition, Sal induces mitochondrial dysfunction and increases mitochondrial ROS levels, which activates autophagy and triggers autophagic degradation of FTH1. Taken together, we revealed that NCOA4 is a new target for Sal-anchored GC and that Sal may be a potential therapeutic drug for the treatment of GC.
研究领域:
肿瘤学
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分子生物学
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药理学
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高影响因子
Advanced Science
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2021
·Vol. 8
·期 10
·2004680
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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.
研究领域:
干细胞生物学
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分子遗传学
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细胞病理学
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肝病学
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高影响因子
Advanced Healthcare Materials
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2021
·Vol. 10
·期 21
·2100683
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IF 9.933
Tiantian Zuo,Tianxu Fang,Jun Zhang,Jie Yang,Rui Xu,Zhihua Wang,Huizi Deng,Qi Shen
Ferritin internalized into tumor cells is degraded and releases iron ions via ferritinophagy. Iron ions participate in Fenton reaction to produce reactive oxygen species for lipid peroxidation and ferroptosis. Inhibition of indoleamine-2,3-dioxygenase (IDO) decreases tryptophan elimination to induce T cells activation for tumor immunosuppression relief. The active tumor targeting nanoparticles containing ferritin and a pH-sensitive molecular-switch (FPBC@SN) are developed to utilize ferritinophagy-cascade ferroptosis and tumor immunity activation for cancer therapy. FPBC@SN disintegrates in acidic cytoplasm and releases sorafenib (SRF) and IDO inhibitor (NLG919). SRF upregulates nuclear receptor coactivator 4 (NCOA4) to induce ferritin and endogenous iron pool degradation by ferritinophagy, then obtained iron ions participate in the Fenton reaction to produce lipid peroxide (LPO). Meanwhile, SRF blocks glutathione synthesis to downregulate glutathione peroxidase 4 (GPX4) which can scavenge LPO as a different pathway from ferritinophagy to promote ferroptosis in tumor cells. NLG919 inhibits IDO to reduce tryptophan metabolism, so immunity in tumors is aroused to anti-tumor. In vitro and in vivo experiments prove FPBC@SN inhibits tumor cell growth and metastasis, indicating the potential of FPBC@SN for breast cancer therapy based on the combination of ferritinophagy-cascade ferroptosis and tumor immunity activation.
研究领域:
癌症生物学
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纳米技术
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药学
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免疫学
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生物化学
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高影响因子
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