Cell Metabolism
·
2025
·
IF 30.9
Zezhao Chen,Xiaosong Gu,Hongbo Chen,Huijing Zhang,Jianping Liu,Xiaohua Yang,Yuping Cai,Mengmeng Zhang,Lingjie Yan,Yuanxin Yang,Bing Shan,Zheng-Jiang Zhu,Yixiao Zhang,Jinyang Gu,Daichao Xu
The capacity of cells to sense and respond to nutrient availability is essential for metabolic homeostasis. Failure in this process may cause cell death and associated diseases. While nutrient sensing in metabolic pathways is well understood, the mechanisms linking nutrient signals to cell death remain unclear. Here, we show that RIPK1, a key mediator of cell death and inflammation, senses methionine and its metabolite, S -adenosylmethionine (SAM), to dictate cell survival and death. SAM-mediated symmetrical dimethylation at RIPK1 Arg606 by PRMT5 functions as a physiological protective brake against RIPK1 activation. Metabolic perturbations, such as methionine restriction or disrupted one-carbon flux, reduce SAM levels and unmask Arg606, promoting RIPK1 self-association and trans -activation, thereby triggering apoptosis and inflammation. Thus, RIPK1 is a physiological SAM sensor linking methionine and one-carbon metabolism to the control of life-or-death decisions. Our findings suggest that RIPK1 could be a potential target for diseases associated with disrupted SAM availability.
研究领域:
生物化学
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分子生物学
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细胞生物学
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DOI
PubMed
高影响因子
Journal of Advanced Research
·
2025
·
IF 13
Longchen Yu,Qining Guo,Yaping Li,Mai Mao,Zhenping Liu,Tingting Li,Lei Wang,Xin Zhang
Introduction Pancreatic cancer (PC) cannot currently be completely cured and has a poor prognosis. Necroptosis is a distinct form of regulated cell death that differs from both necrosis and apoptosis. Understanding the role of necroptosis during PC progression would open new avenues for targeted therapy. Objectives The purpose of this study is to examine the impact of necroptosis on the progression of PC and related mechanisms. Methods RNA sequencing was performed to identify necroptosis-related genes that are differentially expressed in PC tissues. The biological functions of CHMP4C and its necroptosis effects were determined in vitro and in vivo . RNA immunoprecipitation, MeRIP-qPCR, Co-immunoprecipitation assays were conducted to evaluate the interaction among CHMP4C, YBX1 and caspase-8 mRNA. Extracellular vesicles were isolated using the differential ultracentrifugation method. The expression of CHMP4C, p-MLKL and CD117 were detected on a PC tissue microarray using multiplex immunofluorescence staining. Results CHMP4C was significantly overexpressed in PC cells and tissues. It promoted cell growth and suppressed necroptosis of PC cells in both in vivo and in vitro settings. Mechanistically, CHMP4C interacted with YBX1 to mediate m 5 C modification of caspase-8 mRNA, resulting in increased caspase-8 expression and inhibition of RIPK1/RIPK3/MLKL pathway phosphorylation. Furthermore, CHMP4C promoted extracellular exocytosis of p-MLKL to further suppress necroptosis. Additionally, PC cells used CHMP4C within extracellular vesicles to recruit and stimulate mast cells (MCs), which in turn promoted PC cell proliferation. In PC tissues, the expression of CHMP4C showed a negative correlation with p-MLKL and a positive association with CD117. High expression levels of CHMP4C in patients were associated with poorer overall survival outcomes. Conclusions CHMP4C promotes PC progression by inhibiting necroptosis, which has potential as a biomarker and therapeutic target in PC.
研究领域:
肿瘤学
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分子生物学
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医学
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DOI
PubMed
高影响因子
EUROPEAN JOURNAL OF PHARMACOLOGY
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2022
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IF 5.195
Yi-sheng Zeng,Jian Peng,Xiao-fang Gao,Dong Tian,Wei Zhan,Jin Liu,Xiao-jun Hu,Sheng Huang,Shu-ting Tian,Lan Qiu,Ai-ling Liang,Fu-yu Wang,Ren-han Dong,Bing Guang,Tai Yang
As a key mediator of cell death and inflammation, receptor-interacting protein kinase 1 (RIPK1) responds to a broad set of inflammatory and pro-death stimuli in human diseases. Inhibitors targeting RIPK1 are being investigated for the treatment of a wide range of human diseases, including ulcerative colitis . In the present study, we designed, synthesized, and investigated the anti-necroptosis and RIPK1-inhibition effects of SZ-15—a symmetrical high-molecular-weight (>500 Da) compound. SZ-15 effectively inhibited necroptosis in U937 and HT-29 cells at concentrations of 1 nM and 10 nM, respectively, and SZ-15 at a concentration of 10 nM almost completely blocked RIPK1, RIPK3, and mixed-lineage kinase domain-like (MLKL) protein phosphorylation induced by necrosis inducers. SZ-15 suppressed the pro-necroptosis function of RIPK1 by downregulating the mRNA expression of pro-inflammatory cytokines, including tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-6. The activities of SZ-15 were effectively restricted to the gut: The percent recovery of the parent form of SZ-15 in mouse feces was 85.75%. Nevertheless, SZ-15 was effectively absorbed and detected in colon tissues after 1 h at a concentration of 3335 ± 868 ng/g, indicating that membrane permeability was maintained. SZ-15 alleviated dextran sulfate sodium (DSS)-induced ulcerative colitis in vivo by decreasing TNF-α, IL-1β, IL-22, and IL-6 mRNA expression in colonic tissues. Our preclinical study describes a novel gut-restricted RIPK1 inhibitor that shows great potential for use in the clinical treatment of ulcerative colitis.
研究领域:
药理学
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免疫学
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胃肠病学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
MOLECULAR CELL
·
2024
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IF 14.5
Na Zhang,Jianping Liu,Rui Guo,Lingjie Yan,Yuanxin Yang,Chen Shi,Mengmeng Zhang,Bing Shan,Wanjin Li,Jinyang Gu,Daichao Xu
Tumor necrosis factor (TNF)-induced receptor-interacting serine/threonine protein kinase 1 (RIPK1)-mediated cell death, including apoptosis and necroptosis, is increasingly recognized as a major driver of inflammatory diseases. Cell death checkpoints normally suppress RIPK1 kinase to safeguard the organism from its detrimental consequences. However, the mechanisms licensing RIPK1 kinase activity when a protective checkpoint is disabled remain unclear. Here, we identified S -palmitoylation as a licensing modification for RIPK1 kinase. TNF induces RIPK1 palmitoylation, mediated by DHHC5 and dependent on K63-linked ubiquitination of RIPK1, which enhances RIPK1 kinase activity by promoting the homo-interaction of its kinase domain and promotes cell death upon cell death checkpoint blockade. Furthermore, DHHC5 is amplified by fatty acid in the livers of mice with metabolic dysfunction-associated steatohepatitis, contributing to increased RIPK1 cytotoxicity observed in this condition. Our findings reveal that ubiquitination-dependent palmitoylation licenses RIPK1 kinase activity to induce downstream cell death signaling and suggest RIPK1 palmitoylation as a feasible target for inflammatory diseases.
研究领域:
免疫学
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细胞生物学
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分子生物学
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炎症研究
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产品关联
DOI
PubMed
高影响因子
INTERNATIONAL IMMUNOPHARMACOLOGY
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2022
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IF 5.714
Xue-qi Liu,Ming-ming Liu,Ling Jiang,Li Gao,Yao Zhang,Yue-bo Huang,Xian Wang,Wei Zhu,Han-xu Zeng,Xiao-ming Meng,Yong-gui Wu
Acute kidney injury (AKI) is marked by a fast deterioration of the kidney function that may be caused by a variety of factors. Recently, although our group found that PPBICA alleviated programmed cell death in AKI, poor water solubility limited its bioavailability. In this research, we screened a series of derivatives and found that C-316-1 had the best suppressive effect on preventing necroptosis and inflammation in cisplatin- and ischemia/reperfusion-induced AKI in vitro and in vivo with lower toxicity and better water solubility. Mass spectrometry results showed that C-316-1 bound to heat shock protein 90 (Hsp90), which was further confirmed by molecular docking and surface plasmon resonance. Additionally, the Hsp90 expression was upregulated in the blood and tissues of AKI patients. We discovered that C-316-1 decreased the RIPK1 protein level without affecting its mRNA expression. The proteasome inhibitor, MG132 restored the level of RIPK1 reduced by C-316-1, suggesting that C-316-1 limits necroptosis by promoting the degradation of RIPK1 rather than by reducing its production. Immunoprecipitation further showed that pretreatment with C-316-1 disrupted the Hsp90-Cdc37 protein–protein Interactions (PPIs). Thereby, C-316-1 inhibited the Hsp90-Cdc37 complex formation and led to a significant decrease in RIPK1, which in turn reduced necroptosis. Moreover, C-316-1 treatment did not protect against kidney injury in vivo and in vitro when Hsp90 was knocked down and R46, E47, and S50 in Cdc37 binding site of Hsp90 might form an important active pocket with C-316-1. These findings suggest that C-316-1 is a potential therapeutic agent against RIPK1-Mediated Necroptosis in AKI.
研究领域:
药理学
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肾病学
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分子生物学
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细胞生物学
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产品关联
DOI
PubMed
高影响因子
SCIENCE OF THE TOTAL ENVIRONMENT
·
2025
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IF 8
Jing Lu,Hongdi Wei,Xinyu Yao,Yuelin Chen,Meitong Liu,Shuang Guan
Glycidol is a common food contaminant, and its main target organ is the kidney. However, the mechanism of nephrotoxicity of glycidol has not been fully elucidated. In this paper, we investigated the mechanism of glycidol toxicity in mice kidneys and NRK-52E cells. We found that glycidol exposure induced necroptosis in renal cells through the RIPK1/RIPK3/MLKL pathway. Mechanistically, it was further found that glycidol blocked renal cell autophagy and induced ectopic aggregation of p62. Accumulated p62 recruited RIPK1 and activated downstream RIPK1/RIPK3/MLKL necrosome production. At the same time, the accumulated p62 could also participate in the activation of intracellular NF-κB nuclear transcription factor by interacting with RIPK1 to form a signalling complex, which promoted the secretion of inflammatory factors TNF-α and IL-1β, and induced inflammation in the kidney. Our present study provided a new understanding of the complex mechanism of glycidol on renal injury.
研究领域:
毒理学
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细胞生物学
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分子生物学
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DOI
PubMed
高影响因子
Cell Death Discovery
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2022
·Vol. 8
·期 1
·1-13
·
IF 7.109
Lian Ni,Chen Yujie,Chen Sihan,Xiao Ta,Song Changjun,Ke Yangying,Wei Xuecui,Gong Chunyan,Yu Hui,Gu Heng,Chen Qing,Li Min,Chen Xu
Keratinocyte necroptosis (with proinflammatory characteristic) is required for epidermal damage in contact hypersensitivity (CHS). In DNCB-induced CHS mice model, we observed the aggravated keratinocyte death and increased phosphorylation level of MLKL, RIPK3 and RIPK1. However, CHS skin lesion did not present in keratinocyte-specific Mlkl knockout mice. We validated that MLKL-mediated keratinocyte necroptosis is required for epidermal damage in response to immune microenvironment in CHS. Moreover, MLKL-mediated necroptosis deficiency or inhibition resulted in blocking recruitment and activation of inflammatory cells in CHS via reducing HMGB1 release in keratinocytes. This study suggests that MLKL-mediated keratinocyte necroptosis functions as a self-amplified actor in inflammatory responses and could be considered as an effective therapeutic target. It proposes an innovative prospective that inhibiting keratinocyte necroptosis can prevent the development of epidermal damage in CHS.
研究领域:
免疫学
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细胞生物学
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皮肤病学
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DOI
PubMed
高影响因子
ENVIRONMENTAL SCIENCE AND POLLUTION RESEARCH
·
2022
·Vol. 30
·期 1
·1060-1071
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IF 5.19
Zhang Xinyu,Sun Kexin,Wang Xu,Shi Xu,Gong Duqiang
Chlorpyrifos (CPF), an organophosphorus pesticide, is detected commonly in environments, where it is thought to be highly toxic to non-target organisms. However, the mechanism of CYP450s pathway mediated by nuclear receptors on CPF-induced apoptosis and necroptosis at the cellular level and the effect of CPF on the cytotoxicity of the chicken hepatocarcinoma cell line (LMH) has also not been reported in detail. Therefore, this experiment aims to explore whether CPF can improve apoptosis and necroptosis in LMH cells by activating the nuclear receptors/CYP450s axis. LMH cells, the subject of this study, were exposed to 5 μg/mL, 10 μg/mL, and 15 μg/mL doses of CPF. With the increase of CPF concentration, the increase of nuclear receptor level led to the up-regulation of CYP450s activity. With the massive production of ROS, the expression of apoptotic pathway genes (Bax, Caspase9, and Caspase3) enhanced, while Bcl-2 expression dropped sharply. The expression of programmed necroptosis genes (RIPK1, RIPK3, and MLKL) heightened, and Caspase8 reduced considerably. In short, our data suggests that excessive activation of nuclear receptors and CYP450s induced by CPF promotes ROS production, which directs apoptosis and programmed necroptosis in LMH cells. Graphical abstract
研究领域:
毒理学
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细胞生物学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
PESTICIDE BIOCHEMISTRY AND PHYSIOLOGY
·
2023
·
IF 4.7
Naixi Yang,Jinming Guo,Hao Wu,Meichen Gao,Shiwen Xu
Chlorpyrifos (Diethoxy-sulfanylidene-(3,5,6-trichloropyridin-2-yl) oxy-λ 5 -phosphane, CPF) was extensively used organophosphorus pesticide , extensively deteriorating public problem with the enrichment in the water bodies. Eucalyptol (1,3,3-Trimethyl-2-oxabicyclo[2.2.2] octane, EUC), a colorless cyclic monoterpene oxide, has shown anti-inflammatory and anti-oxidation properties. To explore the effect of EUC on CPF-induced necroptosis in the grass carp liver cells (L8824 cells), we treated L8824 cells with 60 mM CPF and 5 μM EUC for 24 h. The results showed that CPF exposed lead to excessive accumulation of reactive oxygen species (ROS) and oxidative stress , activating the NF-κB and RIPK1 pathway, increasing the level of cell necroptosis. However, EUC treatment attenuated the toxic effects of CPF treatment on L8824 cells. In summary, the study demonstrated that CPF induced necroptosis and inflammation, and EUC treatment could decrease CPF-caused cell injury.
研究领域:
环境毒理学
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细胞生物学
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药理学
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产品关联
DOI
PubMed
高影响因子
ONCOLOGY REPORTS
·
2025
·Vol. 53
·期 3
·1-14
·
IF 3.9
Dongsheng Lv,Xu Han,Liang Hao,Zhimin Sun,Aobo Zhang,Jing Liu,Liang Liu,Liqiang Liu
Cysteine‑ and glycine‑rich protein 2 (CSRP2) are closely associated with tumor invasion and metastasis. CSRP2 is significantly upregulated in glioma tissues and is associated with the clinical stage of the tumor. Overexpression of CSRP2 in glioma cells promotes the proliferation and metastasis of cancer cells, whereas CSRP2 knockdown inhibits the biological functions of tumor cells. Transcriptome sequencing of CSRP2‑knockdown U251M cells revealed that silencing of CSRP2 inhibited the JAK‑STAT1 signaling pathway, and differentially expressed genes were significantly enriched in cell processes related to necroptosis. Experiments on necroptosis in glioma cells using flow cytometry, Hoechst 33342/PI dual staining and transmission electron microscopy indicated that CSRP2 overexpression inhibited necroptosis in glioma cells. Western blotting results showed that overexpression of CSRP2 activated the JAK‑STAT1 signaling pathway, while the addition of the pathway inhibitor ruxolitinib promoted the phosphorylation of necroptosis proteins RIPK1, RIPK3 and MLKL. Therefore, it was hypothesized that CSRP2 maintains JAK‑STAT1 activation by inhibiting the protein inhibitor of activated STAT1, which then inhibits the necrotizing apoptosis of glioma cells.
研究领域:
肿瘤学
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细胞生物学
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分子生物学
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神经肿瘤学
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产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）