BIOCHEMICAL PHARMACOLOGY
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2025
·
IF 5.6
Tianfeng Yang,Suyu Zhang,Kun Nie,Xiuhong Peng,Jian Huo,Xiao Fu,Yanmin Zhang
Although ferroptosis as an emerging way exhibits tremendous promising in the therapy of hepatocellular carcinoma (HCC), the novel therapeutic agents targeting ferroptosis are still scarce. In our previous study, we found that the natural products toosendanin (TSN) possessed significant anti-proliferative efficacy by regulating WW domain-containing oxidoreductase (WWOX) in HCC. However, there is very limited understanding about TSN-induced ferroptosis, and the role of WWOX in ferroptosis has not been studied. In present study, we investigated the effect and underlying molecular mechanisms of TSN in WWOX-mediated ferroptosis in HCC. We found that TSN induced ferroptosis in HCC cells and its effect was dependent on WWOX. RNA-seq and RT-qPCR assay identified that TSN significantly increased spermidine/spermine N1-acetyltransferase 1 (SAT1) expression while decreased solute carrier family 40 member 1 (SLC40A1) expression, which play vital roles in ferrous ion transport. Further dual-luciferase reporter assay and Co-IP assay revealed that TSN-induced WWOX activation controlled the transcriptional activity of p53 and NF-E2-related factor 2 (NRF2) by regulating their interaction. Meanwhile, IF assay and WB assay confirmed that TSN increased the nuclear distribution of p-WWOX and p-p53 dimers, but impeded the nuclear translocation of NRF2 by inducing its ubiquitination degradation, ultimately regulating the transcription of their downstream target genes. In addition, the results from cell viability assay and the tumor xenograft model verified that co-treatment of TSN, ML385 (NRF2 inhibitor), and MIRA-1 (p53 activator) could effectively inhibit HCC cells growth in the presence of Fer-1 (ferroptosis inhibitor) in vitro and in vivo. Overall, our study contributes to the necessary understanding of the molecular mechanisms of WWOX-mediated ferroptosis regulation, and identifies TSN as a potential therapeutic agent targeting ferroptosis for HCC.
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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产品关联
DOI
PubMed
高影响因子
Nature Communications
·
2025
·Vol. 16
·期 1
·1-14
·
IF 15.7
Tong Li,Wang Jie,Ma Yunjin,Wang Chunying,Fu Yue,Li Qi,Gao Chengjiang,Song Hui,Qin Ying,Zhao Chunyuan,Zhao Wei
Viruses rely on intracellular materials, including iron, to complete their life cycles and iron withholding may limit viral infections. However, the mechanisms through which viruses disrupt host iron homeostasis and the impact of intracellular iron on the host’s antiviral defense aren’t well studied. Here we show that viral infections facilitate the polyubiquitination and degradation of ferroportin (FPN1, the only cellular iron exporter) by upregulating the host E3 ubiquitin ligase DTX3L, leading to an elevation in cellular iron levels. Excessive ferrous iron suppresses type I IFN responses and autophagy by promoting TBK1 hydroxylation and STING carbonylation in macrophages. FPN1 deficiency suppresses host antiviral defense and facilitates viral replication in vitro and in vivo, while DTX3L deficiency has the opposite effect. These results reveal that viruses hijack host FPN1 to disrupt iron withholding and achieve immune escape, and suggest that iron homeostasis maintained by FPN1 is required for the optimal activation of TBK1- and STING-dependent antiviral responses.
研究领域:
微生物学
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免疫学
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生物化学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
Food & Function
·
2021
·Vol. 12
·期 24
·12671-12682
·
IF 5.396
Jing-yi Ren,Bo-wen Yin,Xiang Li,Si-qi Zhu,Jin-liang Deng,Yi-ting Sun,Zhen-ao Zhang,Zi-hao Guo,Huan-ting Pei,Fan Zhang,Rui-qiang Li,Feng-ge Chen,Yu-xia Ma
Objective: This study aimed to elucidate the pharmacological effects of sesamin (Ses) and its mechanism of action towards PM2.5-induced cardiovascular injuries. Method: Forty Sprague Dawley (SD) rats were randomly divided into five groups: a saline control group; a PM2.5 exposure group; and low-, middle-, and high-dose Ses pretreatment groups. The SD rats were pretreated with different concentrations of Ses for 21 days. Afterward, the rats were exposed to ambient PM2.5 by intratracheal instillation every other day for a total of three times. The levels of inflammatory markers, including tumor necrosis factor-alpha (TNF-α), interleukin-1beta (IL-1β), and interleukin-6 (IL-6), and indicators related to oxidative responses, such as total superoxide dismutase (SOD), reduced glutathione (GSH), glutathione peroxidase (GSH-Px), and malondialdehyde (MDA), were measured in the blood and heart. The expression of ferroptosis-related proteins in heart tissues was determined via western blot and immunohistochemistry. Results: Ses pretreatment substantially ameliorated cardiovascular injuries in rats as evidenced by the decrease in the pathological score and collagen area. The decreased levels of SOD, GSH, and GSH-Px in the heart and serum were inhibited by Ses. In addition, Ses not only notably increased the activity of antioxidant enzymes but also reduced the levels of MDA, CK, LDH, CK-MB, IL-6, TNF-α, IL-1β, and IL-6. Furthermore, Ses pretreatment upregulated the expression levels of GPX4, SLC7A11, TFRC, and FPN1 and inhibited the expression levels of FTH1 and FTL. Conclusion: Ses pretreatment could ameliorate PM2.5-induced cardiovascular injuries perhaps by inhibiting ferroptosis. Therefore, Ses pretreatment may be a novel strategy for the prevention and treatment of PM2.5-induced cardiovascular injury.
研究领域:
药理学
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心脏病学
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毒理学
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环境健康
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DOI
PubMed
高影响因子
BIOLOGICAL TRACE ELEMENT RESEARCH
·
2019
·Vol. 197
·期 2
·580-590
·
IF 2.431
Zhang Jian,Huang Wanyue,Xu Feibo,Cao Zheng,Jia Fubo,Li Yanfei
Aluminum (Al) alters iron regulatory factors content and leads to the changes in iron-related proteins causing iron accumulation. But limited evidence ascertains this hypothesis. Therefore, our experiment was conducted and four groups of male Wistar rats were orally administrated of 0, 50, 150, and 450 mg/kg BW/d aluminum chloride (AlCl 3 ) for 90 days by drinking water, respectively. The cognitive function, pathological lesion of hippocampus, oxidative stress, as well as iron-related proteins and iron regulatory factors expression were detected. The results showed that AlCl 3 remarkably induced the oxidative stress and pathological lesion in the hippocampus and impaired the learning-memory ability. The contents of Al and iron increased in all AlCl 3 -exposed groups. Meanwhile, the increased divalent metal transporter 1 (DMT1) expression enhanced iron import and the decreased ferroportin 1 (Fpn1) expression reduced iron export in AlCl 3 -exposed groups. The iron accumulated and ferritin heavy chains (Fth) expression decreased in all AlCl 3 -exposed groups led to an increase in free iron. The study also showed that iron regulatory factor iron regulatory protein 2 (IRP2) was decreased and hepcidin was increased in AlCl 3 -exposed groups. The results indicated that AlCl 3 induces iron dyshomeostasis presenting as iron accumulation, the disordered expression of iron import, export, store, and regulatory proteins in rat hippocampus accompanied with oxidative stress, pathological lesion, and impaired learning-memory ability.
研究领域:
神经毒理学
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药理学
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分子生物学
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神经科学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
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