Cell Death Discovery
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2025
·Vol. 11
·期 1
·1-17
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IF 7
Wei Guojiang,Huang Ying,Li Wenya,Xie Yuxin,Zhang Deyi,Niu Yuanjie,Zhao Yang
Metabolic reprogramming in prostate cancer has been widely recognized as a promoter of tumor progression and treatment resistance. This study investigated its association with ferroptosis resistance in prostate cancer and explored its therapeutic potential. In this study, we identified differences in the epithelial characteristics between normal prostate tissue and tissues of various types of prostate cancer using single-cell sequencing. Through transcription factor regulatory network analysis, we focused on the candidate transcription factor, SREBF1. We identified the differences in SREBF1 transcriptional activity and its association with ferroptosis, and further verified this association using hdWGCNA. We constructed a risk score based on SREBF1 target genes associated with the biochemical recurrence of prostate cancer by combining bulk RNA analysis. Finally, we verified the effects of the SREBPs inhibitor Betulin on the treatment of prostate cancer and its chemosensitization effect. We observed characteristic differences in fatty acid and cholesterol metabolism between normal prostate tissue and prostate cancer tissue, identifying high transcriptional activity of SREBF1 in prostate cancer tissue. This indicates that SREBF1 is crucial for the metabolic reprogramming of prostate cancer, and that its mediated metabolic changes promoted ferroptosis resistance in prostate cancer in multiple ways. SREBF1 target genes are associated with biochemical recurrence of prostate cancer. Finally, our experiments verified that SREBF1 inhibitors can significantly promote an increase in ROS, the decrease in GSH, and the decrease in mitochondrial membrane potential in prostate cancer cells and confirmed their chemosensitization effect in vivo. Our findings highlighted a close association between SREBF1 and ferroptosis resistance in prostate cancer. SREBF1 significantly influences metabolic reprogramming in prostate cancer cells, leading to ferroptosis resistance. Importantly, our results demonstrated that SREBF1 inhibitors can significantly enhance the therapeutic effect and chemosensitization of prostate cancer, suggesting a promising therapeutic potential for the treatment of prostate cancer.
研究领域:
肿瘤学
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分子生物学
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生物信息学
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PubMed
高影响因子
FUNCTIONAL & INTEGRATIVE GENOMICS
·
2021
·Vol. 21
·期 5
·557-570
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IF 3.41
Sun Shouxiang,Cao Xiaojuan,Castro L. Filipe C.,Monroig Óscar,Gao Jian
Obesity is a rapidly growing health pandemic, underlying a wide variety of disease conditions leading to increases in global mortality. It is known that the phosphorylation of various proteins regulates sterol regulatory element-binding transcription factors 1 ( srebf1 ), a key lipogenic transcription factor, to cause the development of obesity. To detect the key protein kinases for regulating srebf1 in lipid deposition, we established the srebf1 knockout model in zebrafish (KO, srebf1 −/− ) by CRISPR/Cas9. The KO zebrafish exhibited a significant reduction of total free fatty acid content (fell 60.5%) and lipid deposition decrease compared with wild-type (WT) zebrafish. Meanwhile, srebf1 deletion in zebrafish eliminated lipid deposition induced by high-fat diet feeding. Compared with WT zebrafish, a total of 697 differentially expressed proteins and 316 differentially expressed phosphoproteins with 439 sites were identified in KO by differential proteomic and phosphoproteomic analyses. A significant number of proteins identified were involved in lipid and glucose metabolism. Moreover, some protein kinases critical for regulating srebf1 in lipid deposition, including Cdk2, Pkc, Prkceb, mTORC1, Mapk12, and Wnk1, were determined by network analyses. An in vitro study was performed to verify the network analysis results. Our findings provide potential targets (kinases) for human obesity treatments.
研究领域:
分子生物学
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遗传学
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蛋白质组学
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代谢
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营养学
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肥胖研究
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PubMed
高影响因子
Frontiers in Cell and Developmental Biology
·
2026
·
IF 5.3
Xiaoying Chen,Guanyi Zheng,Kailong Fu,Minglong Yao,Kan Lin
Objective This study was designed to elucidate the molecular pathways responsible for anti-atherosclerotic effects of the traditional Chinese medicine formula Yishen Huoxue Huatan, with a focus on its key active component sesamin. Methods Network pharmacology was applied to predict potential targets and pathways associated with the anti-atherosclerotic activity of Yishen Huoxue Huatan. An atherosclerosis model was constructed in ApoE −/− mice treated with sesamin (50 or 100 mg/kg), and endothelial injury was induced in human umbilical vein endothelial cells (HUVECs) using oxidized low-density lipoprotein (ox-LDL). Aortic pathology, lipid profiles, m 6 A RNA methylation levels, iron accumulation, oxidative stress, and ferroptosis-related markers were assessed. Ferrostatin-1 (Fer-1) was used to verify the involvement of ferroptosis in sesamin-mediated endothelial protection. The involvement of the METTL3/SREBF1 axis was further investigated using RT–qPCR, MeRIP–qPCR, mRNA stability assays, and gene-silencing approaches. Results Network pharmacology identified sesamin as a major bioactive constituent associated with atherosclerosis-related and epigenetic regulatory pathways. In ApoE −/− mice, sesamin reduced aortic lipid deposition, alleviated vascular injury, and improved dyslipidemia. In HUVECs, sesamin attenuated ox-LDL–induced endothelial injury, iron overload, lipid peroxidation, and oxidative stress. Fer-1 produced protective effects similar to those of sesamin, supporting the involvement of ferroptosis inhibition in sesamin-mediated endothelial protection. Mechanistically, sesamin downregulated METTL3 expression and reduced m 6 A modification of SREBF1 mRNA, thereby increasing SREBF1 mRNA stability and protein expression. SREBF1 silencing markedly weakened the anti-ferroptotic effects of sesamin, whereas concurrent METTL3 knockdown partially restored this protective phenotype. Conclusion Sesamin upregulates SREBF1 expression by inhibiting METTL3-mediated m 6 A methylation, thereby alleviating ferroptosis-related alterations in vascular endothelial cells and ultimately delaying the progression of atherosclerosis.
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高影响因子
BIOCHEMICAL PHARMACOLOGY
·
2026
·
IF 6.5
Ting Yu,Yongfeng Su,Ping’an Zou,Yan Jian,Yaqi Wang
Malignant melanoma remains a formidable clinical challenge due to its propensity for metastasis and therapeutic resistance. Identifying molecular targets that regulate malignant melanoma progression is critical for developing effective therapies. In this study, we investigated the role of cysteine-rich intestinal protein 1 (CRIP1), a novel oncogene, in melanoma progression. CRIP1 expression was analyzed using public datasets, and functional roles of CRIP1 in proliferation, colony formation, migration, and invasion were assessed via overexpression cell models. Mechanistic insights were gained through RNA sequencing, bioinformatics, 4-phenylbutyric acid (4-PBA) or N-acetylcysteine (NAC) treatment, Western blot, dual-luciferase reporter, and chromatin immunoprecipitation (ChIP). Xenograft models were used to confirm in vivo effects. CRIP1 was significantly upregulated in melanoma tissues, particularly in metastases, and correlated with an endoplasmic reticulum (ER) stress gene signature. CRIP1 overexpression promoted malignant phenotypes in vitro and tumor growth in vivo, which was dependent on the activation of ER stress. Integrative analysis identified SREBF1 (Sterol Regulatory Element Binding Transcription Factor 1) as a downstream target. CRIP1 increased intracellular ROS levels by promoting SREBF1 expression, thereby activating ER stress and promoting malignant phenotypes in melanoma cells. Mechanistically, CRIP1 promoted NFATC2 (nuclear factor of activated T cells 2) binding to the SREBF1 promoter to drive transcription of SREBF1. These findings indicate that CRIP1 serves as a critical driver of melanoma progression through ER stress activation and identify a novel CRIP1/NFATC2/SREBF1 axis, providing insights into the role of CRIP1 in melanoma biology and presenting new potential therapeutic targets for this aggressive malignancy.
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高影响因子
TOXICOLOGY
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2016
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IF 3.817
Xu Wang,Yijie Bai,Guyue Cheng,Awais Ihsan,Feng Zhu,Yulian Wang,Yanfei Tao,Dongmei Chen,Menghong Dai,Zhengli Liu,Zonghui Yuan
Quinoxaline 1,4-dioxides (QdNOs) are widely used as a kind of antibacterial growth promoter in animal husbandry. The adrenal cortex was found to be one of the main toxic targets of QdNOs, accompanied by a decreased aldosterone level. However, the way in which QdNOs decrease production of the hormone aldosterone is far from clear. To illustrate the mechanism by which QdNOs damage the adrenal cortex and decrease aldosterone hormone levels, the QdNOs were screened to choose the drug with most toxic effects on aldosterone production, and then to reveal the mechanism between the gene and protein profiles in human adrenocortical cells (NCI-H295R cells). The results found that quinocetone (QCT) showed the highest adrenal toxic effect among QdNOs. After exposing H295R cells to 10 and 20 μM QCT for 24 h, compared with blank cells, the gene and protein expression profiles obtained were analyzed by microarray and MALDI TOF/TOF mass spectrometry, respectively. The results of microarray analysis suggested that ABCG1 and SREBF1, which were involved in the cholesterol biosynthetic and metabolic processes, and CYP17A1, NR4A2 and G6PD, which were related to aldosterone biosynthesis, were important molecular targets. It has been speculated that PKC and ERK pathways might be involved in the reduction of aldosterone production caused by QCT, through enhanced mRNA expression of CYP17A1. Additionally, JNK and p38MAPK signal transduction pathways might participate in apoptosis induced by QCT. Twenty-nine and 32 protein spots were successfully identified when cells were treated with 10 and 20 μM QCT, respectively. These identified proteins mainly included material synthesis and energy metabolism-related proteins, transcription/translation processing-related proteins, signal transduction proteins, cytoskeletal proteins, molecular chaperones, proteins related to response to stress, and transport proteins. Further investigations suggested that oxidative stress caused by QCT was exacerbated through disruption of the Keap1/Nrf2/ARE anti-oxidative stress pathway. Taken together, the data demonstrated for the first time that the Keap1/Nrf2/ARE pathway plays a crucial role in adrenal toxicity, and that CYP17A1 was the key switch to reduce the aldosterone production induced by QCT. Furthermore, large numbers of genes and proteins and entry points for research in the inhibition of aldosterone synthesis induced by QCT were offered, which will provide new insight into the adrenal toxicity of QdNOs and help to provide a theoretical foundation for the formulation of safety controls for products obtained from animals and to design new QdNOs with less harmful effects.
研究领域:
毒理学
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药理学
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内分泌学
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分子生物学
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细胞生物学
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PubMed
高影响因子
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