BIOCHEMICAL PHARMACOLOGY
·
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
CELLULAR ONCOLOGY
·
2023
·
IF 6.6
Wei Wanhui,Lu Yuanyuan,Hu Qian,Yin Jinwen,Wang Youwei,Zhang Heng,Zhao Qiu,Liu Lan
Purpose The combination of cisplatin and gemcitabine-based chemotherapy has been recommended as a preferred regimen for pancreatic ductal adenocarcinoma (PDAC) patients with germline-based mutations. However, the underlying mechanism remains poorly elucidated. Therefore, our study aimed to explore the mechanistic basis of the cell-killing activity of gemcitabine plus cisplatin and identify potential therapeutic targets. Methods First, we explored the synergistic cytotoxic effects of gemcitabine and cisplatin on PDAC through in vitro and in vivo experiments. Then, we investigated ferroptosis-related biomarkers, to assess the impact of the combination therapy on ferroptosis. Using bioinformatics methods, we identified SAT1 as a potential key mediator of ferroptosis induced by gemcitabine and cisplatin. We tested the polyamine levels in PDAC cells by LC–MS after overexpressed or knocked down SAT1, and explored the role of polyamines in ferroptosis using exogenous supplementation. Finally, we explored the regulatory effect of Sp1 on SAT1 through ChIP-qPCR and dual-luciferase reporter assay. Results Gemcitabine plus cisplatin enhanced cell death and induced ferroptosis in PDAC. This combination upregulated SAT1 transcription by inhibiting Sp1. SAT1 activation promoted the catabolism of spermine and spermidine, leading to iron accumulation and lipid peroxide generation, ultimately resulting in ferroptosis. Conclusions In summary, our findings suggested the gemcitabine and cisplatin combination therapy induced ferroptosis in a GSH-independent manner in PDAC. The combined treatment inhibited Sp1 and upregulated SAT1 transcription, leading to the breakdown of spermine and spermidine. Therefore, targeting SAT1-induced polyamine metabolism may represent a promising therapeutic strategy for PDAC.
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
Pharmaceuticals
·
2022
·Vol. 15
·期 10
·1177
·
IF 5.215
Yini Dang,Qing He,Siyu Yang,Huaiqing Sun,Yin Liu,Wanting Li,Yi Tang,Yu Zheng,Ting Wu
Objectives: Despite significant advances in neuroscience, the mechanisms of AD are not fully understood. Single-cell RNA sequencing (scRNA-seq) techniques provide potential solutions to analyze cellular composition of complex brain tissue and explore cellular and molecular biological mechanisms of AD. Methods: We investigated cellular heterogeneity in AD via utilization of bioinformatic analysis of scRNA-seq in AD patients and healthy controls from the Gene Expression Omnibus (GEO) database. The “GOplot” package was applied to explore possible biological processes in oligodendrocytes, astrocytes, and oligodendrocyte progenitor cells (OPCs). Expression patterns and biological functions of differentially expressed genes (DEGs) from scRNA-seq data were validated in RNA sequencing data. DEGs in astrocytes interacted with ferroptosis-related genes in FerrDb. CCK-8 and EdU assays were performed to measure cell proliferation ability. ROS, Fe2+level, mitochondrial membrane potentials, iron concentrations, and total iron binding capacity (TIBC) in serum were evaluated. Y-maze and elevated maze were used to measure anxiety-like behavior. Autonomous and exploration behaviors or learning and memory ability in mice were analyzed using open field test and novel object recognition test. Results: Multiple clusters were identified, including oligodendrocytes, astrocytes, OPCs, neurons, microglia, doublets, and endothelial cells. Astrocytes were significantly decreased in AD, while oligodendrocytes and OPCs increased. Cell-to-cell ligand–receptor interaction analysis revealed that astrocytes, neurons, and OPCs mainly established contacts with other cells via the NRG3–ERBB4 ligand–receptor pair. GO and KEGG analyses found that astrocytes were enriched in the ferroptosis pathway. FTH1 and SAT1 in astrocytes were identified as hub mRNAs associated with ferroptosis. Serum iron concentration of 5xFAD mice was higher than that of WT, and emotional and cognitive function were significantly impaired as compared to WT. Serum iron concentration was negatively correlated with number of astrocytes and percentage of time spent entering the novelty arm in the Y-maze test, while it was positively correlated with percentage of time spent in the central area. Meanwhile, number of astrocytes was negatively correlated with percentage of time spent in the central area, while it was positively correlated with percentage of time spent entering the novelty arm. Conclusions: Through scRNA-seq analysis, we found that ferroptosis was activated in astrocytes and may contribute to the pathophysiological process in the entorhinal cortex. FTH1 and SAT1 were identified to impact astrocyte ferroptosis. Emotional and cognitive impairment in AD was associated with astrocyte ferroptosis. Our findings provide clues to reveal the pathophysiological processes following AD at the cellular level and highlight potential drug targets for the treatment of AD.Keywords:Alzheimer’s disease;single-cell RNA sequencing;astrocytes;ferroptosis
研究领域:
神经科学
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分子生物学
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生物信息学
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神经退行性疾病
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DOI
PubMed
高影响因子
INTERNATIONAL IMMUNOPHARMACOLOGY
·
2024
·
IF 4.8
Feng Chen,Minghua Su,Dong Han,Yifan Wang,Menglong Song
Methyltransferase-like 14 (METTL14) is implicated in the regulation of various inflammatory disorders. However, its function and molecular mechanism in severe acute pancreatitis (SAP) remains unrevealed. Here we reported an increase in METTL14 in the pancreas of SAP mice and cerulein-LPS-treated AR42J cells. METTL14 depletion reversed inflammatory response and ferroptosis by reducing the expression of SAT1 (spermidine/spermine N1-acetyltransferase 1) and ACSL4 (acyl-CoA synthetase long chain family member 4) in an m6A-dependent manner. IGF2BP2 (insulin like growth factor 2 mRNA binding protein 2) could recognize m6A-modified SAT1 and ACSL4 mRNA and enhance their stability. Moreover, METTL14 depletion ameliorated pancreatic injury, inflammation, and ferroptosis induced by SAP. METTL14 overexpression aggravated SAP by promoting ferroptosis in vivo. Therefore, these results demonstrated that METTL14-induced ferroptosis promoted the progression of SAP, and targeting METTL14 or ferroptosis could be a potential strategy for the prevention and treatment of SAP.
研究领域:
分子生物学
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炎症性疾病
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胃肠病学
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DOI
PubMed
高影响因子
HISTOCHEMISTRY AND CELL BIOLOGY
·
2026
·Vol. 164
·期 1
·19
·
IF 2.9
Tang Yingqi,Wang Siyao,Wang Yu,Zhang Tianyuan,Liu Yu,Di Yunhua
Renal tubular damage and interstitial fibrosis are highly linked to diabetic kidney disease (DKD) progression. Ferroptosis in renal tubular epithelial cells has emerged as one of the key mechanisms of DKD. Spermidine/spermine N1-acetyltransferase 1 (SAT1) knockdown has been found to alleviate repetitive low-dose cisplatin-induced kidney damage and fibrosis, and importantly, SAT1 silencing represses cellular sensitivity to ferroptosis. However, the effect of SAT1 on DKD-associated ferroptosis and its potential mechanism remain understood. In this study, we constructed a high-fat diet/streptozotocin-induced DKD mouse model and a high glucose (HG)-injured HK-2 cell model with the aim of verifying whether SAT1 silencing attenuates DKD tubular damage by regulating ferroptosis. We found that SAT1 was upregulated in DKD mouse kidneys and HG-treated HK-2 cells. Significant tubular damage, fibrosis, ferroptosis, and oxidative stress were observed in DKD mouse kidneys. In an in vitro loss-of-function assay, SAT1 silencing suppressed HG-induced HK-2 cytotoxicity, extracellular matrix (ECM) synthesis, and inflammation. Additionally, SAT1 silencing decreased HG-activated MDA and 4-HNE production, while restoring GSH levels. SAT1 silencing also abrogated HG-activated ferroptosis in HK-2 cells, as evidenced by a reduction in iron overload, inhibition of lipid peroxidation, and upregulation of ferroptosis-related protein (SLC7A11, GPX4, and TFR1) expression. Mechanistically, SAT1 silencing facilitated nuclear translocation and expression of NRF2. Impairment of NRF2 function abrogated the inhibitory effects of SAT1 silencing on HG-stimulated HK-2 cytotoxicity, ferroptosis, and ECM accumulation. Overall, the SAT1/NRF2 axis is a critical regulator of tubular damage in DKD, and suppression of SAT1 may be an underlying target for DKD treatment.
✓ 已验证
DOI
PubMed
高影响因子
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