Cell reports最新文献_第2页

Aggrecan protects against plaque accumulation and is essential for proper microglial responses to plaques. 聚集蛋白可以防止斑块积聚，对小胶质细胞对斑块的反应至关重要。

IF 6.9 1区生物学

Cell reports Pub Date : 2025-07-30 DOI: 10.1016/j.celrep.2025.116064

Rocio A Barahona, Nellie E Kwang, Aashna R Kono-Soosaipillai, Giovanna Rubio Salgado, Kristine M Tran, Yueh-Hao Lu, Siddharth Reddy, Celia da Cunha, Eric Velazquez-Rivera, Joshua D Crapser, Xiangmin Xu, Lindsay A Hohsfield, Kim N Green

{"title":"Aggrecan protects against plaque accumulation and is essential for proper microglial responses to plaques.","authors":"Rocio A Barahona, Nellie E Kwang, Aashna R Kono-Soosaipillai, Giovanna Rubio Salgado, Kristine M Tran, Yueh-Hao Lu, Siddharth Reddy, Celia da Cunha, Eric Velazquez-Rivera, Joshua D Crapser, Xiangmin Xu, Lindsay A Hohsfield, Kim N Green","doi":"10.1016/j.celrep.2025.116064","DOIUrl":"https://doi.org/10.1016/j.celrep.2025.116064","url":null,"abstract":"Alzheimer's disease (AD) is a neurodegenerative disease characterized by amyloid plaques and neurofibrillary tangles. Recent evidence implicates extracellular matrix (ECM) dysfunction in disease pathogenesis, including extensive loss of perineuronal nets (PNNs). PNNs are neuron-ensheathing condensed ECM structures composed of chondroitin sulfate proteoglycans, including the main constituent aggrecan (ACAN). To explore the role of PNNs in AD, we utilize the 5xFAD model and genetically target Acan in Nestin-expressing cells, resulting in loss of ACAN and ablation of the PNN structure. In 5xFAD mice, ACAN cKO results in increased plaque deposition, reduced plaque sphericity, and impaired microglia-plaque association. Single-cell spatial transcriptomics identifies an enhanced disease-associated microglia (DAM) phenotype in 5xFAD ACAN cKO mice, which is accompanied by decreased dystrophic neurite formation. Collectively, our data suggest that PNNs may play a crucial role in mediating the microglial response to plaques.","PeriodicalId":9798,"journal":{"name":"Cell reports","volume":"44 8","pages":"116064"},"PeriodicalIF":6.9,"publicationDate":"2025-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144764609","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Innate immune mechanisms hijacked by leukemia-initiating stem cells for selective advantage and immune evasion in Ptpn11-associated JMML. 在ptpn11相关的JMML中，被白血病启动干细胞劫持的先天免疫机制具有选择性优势和免疫逃避。

IF 6.9 1区生物学

Cell reports Pub Date : 2025-07-30 DOI: 10.1016/j.celrep.2025.116087

Hong Zheng, Peng Zhao, Zhenya Tan, Wen-Mei Yu, Juwita Werner, Elliot Stieglitz, Christopher C Porter, Shanmuganathan Chandrakasan, Daniel S Wechsler, Simon Mendez-Ferrer, Cheng-Kui Qu

{"title":"Innate immune mechanisms hijacked by leukemia-initiating stem cells for selective advantage and immune evasion in Ptpn11-associated JMML.","authors":"Hong Zheng, Peng Zhao, Zhenya Tan, Wen-Mei Yu, Juwita Werner, Elliot Stieglitz, Christopher C Porter, Shanmuganathan Chandrakasan, Daniel S Wechsler, Simon Mendez-Ferrer, Cheng-Kui Qu","doi":"10.1016/j.celrep.2025.116087","DOIUrl":"https://doi.org/10.1016/j.celrep.2025.116087","url":null,"abstract":"Juvenile myelomonocytic leukemia (JMML) originates from mutated hematopoietic stem cells. The mechanism by which mutant stem cells are sustained, leading to leukemia development, remains elusive. By comprehensively examining transcriptomic profiles, cell compositions, developmental trajectories, and cell-cell interactions across various stages of tumor cell development in a mouse model of Ptpn11 mutation-associated JMML, we find that Ptpn11E76K/+ mutant stem cells exhibit de novo activation of the myeloid transcriptional program and markedly increased expression of innate immunity-associated antimicrobial peptides and pro-inflammatory proteins, particularly S100a9 and S100a8. Biological experiments confirm that S100a9/S100a8 confer a selective advantage to mutant stem cells through autocrine effects and facilitate immune evasion by recruiting and promoting immune-suppressive myeloid-derived suppressor cells in the microenvironment. Importantly, pharmacological inhibition of S100a9/S100a8 signaling effectively impede leukemia development from Ptpn11E76K/+ mutant stem cells. These findings collectively suggest that JMML-initiating cells exploit innate immune and inflammatory mechanisms to establish clonal dominance.","PeriodicalId":9798,"journal":{"name":"Cell reports","volume":"44 8","pages":"116087"},"PeriodicalIF":6.9,"publicationDate":"2025-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144764611","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Topoisomerase IIIα controls alternative lengthening of telomeres. 拓扑异构酶IIIα控制端粒的选择性延长。

IF 6.9 1区生物学

Cell reports Pub Date : 2025-07-30 DOI: 10.1016/j.celrep.2025.116066

Prashant Khandagale, Yilun Sun, Daiki Taniyama, Sourav Saha, Liton Kumar Saha, Yves Pommier

引用次数: 0

TRIM65 as a key regulator of ferroptosis and glycolysis in lactate-driven renal tubular injury and diabetic kidney disease. TRIM65作为乳酸驱动肾小管损伤和糖尿病肾病中铁下垂和糖酵解的关键调节因子。

IF 6.9 1区生物学

Cell reports Pub Date : 2025-07-30 DOI: 10.1016/j.celrep.2025.116091

Guangyan Yang, Xiaomai Liu, Yanchun Li, Lixing Li, Jiaqing Xiang, Zhen Liang, Meixiu Jiang, Shu Yang

{"title":"TRIM65 as a key regulator of ferroptosis and glycolysis in lactate-driven renal tubular injury and diabetic kidney disease.","authors":"Guangyan Yang, Xiaomai Liu, Yanchun Li, Lixing Li, Jiaqing Xiang, Zhen Liang, Meixiu Jiang, Shu Yang","doi":"10.1016/j.celrep.2025.116091","DOIUrl":"https://doi.org/10.1016/j.celrep.2025.116091","url":null,"abstract":"Recent studies have highlighted the critical role of renal tubular epithelial cell (TEC) damage in the progression of diabetic kidney disease (DKD), where lactate accumulation is closely associated with TEC injury despite unclear mechanisms. This study demonstrates that TRIM65 knockout exacerbates diabetic kidney damage, while TEC-specific overexpression of TRIM65 ameliorates injury. Mechanistically, TRIM65 suppresses ferroptosis by targeting iron-responsive element binding protein 2 (IREB2) for ubiquitin-mediated degradation while also inhibiting glycolysis through ubiquitination and degradation of pyruvate dehydrogenase kinase 4, a key glycolytic regulator. Notably, lactate promotes p300-mediated lactylation of TRIM65 at lysine 206 (K206), which reduces ubiquitin ligase activity. Supplementation of wild-type TRIM65 reverses kidney damage in knockout mice, and overexpression of the lactylation-defective K206R mutant further enhances protective effects against DKD. These findings reveal that lactate-induced lactylation of TRIM65 at K206 impairs its dual regulatory roles in inhibiting ferroptosis and glycolysis, thereby driving DKD progression and identifying therapeutic targets.","PeriodicalId":9798,"journal":{"name":"Cell reports","volume":"44 8","pages":"116091"},"PeriodicalIF":6.9,"publicationDate":"2025-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144764615","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

The histone core domain evolves at single-residue resolution to directly orchestrate transcription. 组蛋白核心结构域在单残基分辨率下进化，直接协调转录。

IF 6.9 1区生物学

Cell reports Pub Date : 2025-07-29 DOI: 10.1016/j.celrep.2025.116079

Zachary H Harvey, Kathryn M Stevens, Jian Yi Kok, Akihisa Osakabe, Jiaying Liu, Tobias Warnecke, Frédéric Berger

{"title":"The histone core domain evolves at single-residue resolution to directly orchestrate transcription.","authors":"Zachary H Harvey, Kathryn M Stevens, Jian Yi Kok, Akihisa Osakabe, Jiaying Liu, Tobias Warnecke, Frédéric Berger","doi":"10.1016/j.celrep.2025.116079","DOIUrl":"https://doi.org/10.1016/j.celrep.2025.116079","url":null,"abstract":"Nucleosomes are thought to be structural barriers to transcription, establishing a restrictive ground state that must be destabilized for gene expression. However, structural insights have revealed that transcription can proceed in the presence of nucleosomes, suggesting that this model is incomplete. Here, we reconstituted H2A.Z sequences resulting from more than a billion years of eukaryotic evolution in a single synthetic host system, interrogating their impact on transcription. We identified single-residue substitutions within the ultra-conserved core domain loop 2 (L2) of H2A.Z as sufficient to confer emergent properties and drive neofunctionalization. Such L2 neomorphs acquired a direct interaction with transcription elongation factor Spt6, rewiring gene expression by tuning polymerase processivity. We conclude that even minimal changes in histone sequences can transform their function, underscoring the evolutionary potential of the histone core domain to drive regulatory innovation and highlighting a previously unappreciated role of the histone core domain in transcriptional regulation.","PeriodicalId":9798,"journal":{"name":"Cell reports","volume":"44 8","pages":"116079"},"PeriodicalIF":6.9,"publicationDate":"2025-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144752533","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Multi-omics analysis reveals single-cell meiotic hotspot dynamics and epigenomic regulations in female mammals. 多组学分析揭示了雌性哺乳动物单细胞减数分裂热点动态和表观基因组调控。

IF 6.9 1区生物学

Cell reports Pub Date : 2025-07-29 DOI: 10.1016/j.celrep.2025.116082

Jingyi Li, Jiansen Lu, Jiayu Chen, Qianzheng Fu, Zhenhuan Jiang, Shaorong Gao, Fuchou Tang

{"title":"Multi-omics analysis reveals single-cell meiotic hotspot dynamics and epigenomic regulations in female mammals.","authors":"Jingyi Li, Jiansen Lu, Jiayu Chen, Qianzheng Fu, Zhenhuan Jiang, Shaorong Gao, Fuchou Tang","doi":"10.1016/j.celrep.2025.116082","DOIUrl":"https://doi.org/10.1016/j.celrep.2025.116082","url":null,"abstract":"Meiotic recombination initiates via DNA double-strand breaks (DSBs) at specialized hotspots, while the regulation of meiotic recombination hotspots in females remain elusive due to the scarcity of embryonic stage germ cells (EGCs). Here, we mapped genome-wide active recombination hotspots and estimated their activities in female EGCs at single-cell resolution, revealing the high variability in hotspot usage frequency among individual germ cells. Further investigation of nucleosome positioning and histone modifications at recombination hotspots revealed that PRDM9-mediated open chromatin and flanking H3K4me3 established earlier at high-frequency hotspots compared with less frequently used ones. Unexpectedly, although recombination hotspots usually distributed outside of heterochromatin, H3K9me3 was clearly enriched around hotspots in females, forming a unique H3K4me3/H3K9me3 bivalent state. And we showed that an appropriate H3K9me3 level may be required for downstream DSB repairs. Together, our results provided understanding about the landscape and epigenomic regulation of recombination hotspots in females.","PeriodicalId":9798,"journal":{"name":"Cell reports","volume":"44 8","pages":"116082"},"PeriodicalIF":6.9,"publicationDate":"2025-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144752532","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

A spatial imaging-transcriptomics paradigm for deciphering the molecular basis of microscopic MRI in the normal brain and Alzheimer's disease. 空间成像-转录组学范式用于破译正常大脑和阿尔茨海默病显微MRI的分子基础。

IF 6.9 1区生物学

Cell reports Pub Date : 2025-07-29 DOI: 10.1016/j.celrep.2025.116073

Yiqi Shen, Yao Shen, Menglei Wang, Kaiyu Jin, Penghui Yang, Zuozhen Cao, Qinfeng Zhu, Zhiyong Zhao, Haotian Li, Lei Han, Shiping Liu, Jie Liao, Jing Zhang, Xiaohui Fan, Dan Wu

{"title":"A spatial imaging-transcriptomics paradigm for deciphering the molecular basis of microscopic MRI in the normal brain and Alzheimer's disease.","authors":"Yiqi Shen, Yao Shen, Menglei Wang, Kaiyu Jin, Penghui Yang, Zuozhen Cao, Qinfeng Zhu, Zhiyong Zhao, Haotian Li, Lei Han, Shiping Liu, Jie Liao, Jing Zhang, Xiaohui Fan, Dan Wu","doi":"10.1016/j.celrep.2025.116073","DOIUrl":"https://doi.org/10.1016/j.celrep.2025.116073","url":null,"abstract":"Imaging genomics offers powerful links between genetics and neuroimaging phenotypes, but conventional methods often lack spatial correspondence. We introduce spatial imaging-transcriptomics, a paradigm that directly integrates magnetic resonance imaging (MRI) and spatially resolved transcriptomics (ST) with matched resolution from the same brain through spatially co-registered maps. We apply this framework to wild-type and Alzheimer's disease (AD) mouse models to uncover the molecular underpinnings of diffusion MRI. In the normal brain, fractional anisotropy (FA) correlates with myelination processes and oligodendrocytes, whereas diffusivity indices are associated with neurons. Furthermore, we identified the genetic basis for observed cortical gradients in diffusion tensor imaging (DTI). In the AD mouse model, reduced FA is linked to myelin and oligodendrocyte change and β-amyloid deposition. Critically, imaging-defined disease foci can guide differential gene expression analysis to uncover AD-specific genetic alterations. The spatial imaging-transcriptomics paradigm provides an unprecedented high-resolution bridge between neuroimaging and transcriptomics, benefitting the decipherment of complex molecular events in brain disorders.","PeriodicalId":9798,"journal":{"name":"Cell reports","volume":"44 8","pages":"116073"},"PeriodicalIF":6.9,"publicationDate":"2025-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144759221","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Antibody-mediated TGF-β1 activation for the treatment of diseases caused by deleterious T cell activity. 抗体介导的TGF-β1活化治疗有害T细胞活性引起的疾病。

IF 6.9 1区生物学

Cell reports Pub Date : 2025-07-29 DOI: 10.1016/j.celrep.2025.116061

Fanny Lambert, Jan Felix, Séverine Wautier, Emilie Dupré, Mathieu Jamez, Camille Michiels, Mélanie Gaignage, Lore Mariën, Manon Lesage, Bas van der Woning, Savvas N Savvides, Sophie Lucas

{"title":"Antibody-mediated TGF-β1 activation for the treatment of diseases caused by deleterious T cell activity.","authors":"Fanny Lambert, Jan Felix, Séverine Wautier, Emilie Dupré, Mathieu Jamez, Camille Michiels, Mélanie Gaignage, Lore Mariën, Manon Lesage, Bas van der Woning, Savvas N Savvides, Sophie Lucas","doi":"10.1016/j.celrep.2025.116061","DOIUrl":"https://doi.org/10.1016/j.celrep.2025.116061","url":null,"abstract":"Transforming growth factor β1 (TGF-β1) is an immunosuppressive cytokine produced as a latent homodimer, in which mature TGF-β1 is encapsulated and kept inactive by the latency-associated peptide (LAP). The transmembrane protein GARP presents latent TGF-β1 on the surface of regulatory T cells (Tregs) to enable activation and release of mature TGF-β1 by integrins. Here, we derived monoclonal antibodies (mAbs) that activate latent TGF-β1 anchored on cells by a transmembrane protein. Biochemical and structural studies by electron cryo-microscopy (cryo-EM) reveal that such mAb-mediated activation requires bivalent binding close to the LAP dimerization interface and crosslinking of two membrane-bound GARP:TGF-β1 complexes on the same cell or across different cells. Administration of mAbs to mice with graft versus host disease reduced disease severity and increased survival. The therapeutic effect required Tregs. Collectively, our findings demonstrate that activation of membrane-bound TGF-β1 in vivo is achievable with mAbs, introducing new immunotherapeutic options for allo- or autoimmune diseases characterized by deleterious T cell activity insufficiently controlled by Tregs.","PeriodicalId":9798,"journal":{"name":"Cell reports","volume":"44 8","pages":"116061"},"PeriodicalIF":6.9,"publicationDate":"2025-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144759272","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Disruption of hippocampal-prefrontal neural dynamics and risky decision-making in a mouse model of Alzheimer's disease. 阿尔茨海默病小鼠模型中海马-前额叶神经动力学和风险决策的破坏。

IF 6.9 1区生物学

Cell reports Pub Date : 2025-07-29 DOI: 10.1016/j.celrep.2025.116081

Eun Joo Kim, Sanggeon Park, Bryan P Schuessler, Harry Boo, Jeiwon Cho, Jeansok J Kim

{"title":"Disruption of hippocampal-prefrontal neural dynamics and risky decision-making in a mouse model of Alzheimer's disease.","authors":"Eun Joo Kim, Sanggeon Park, Bryan P Schuessler, Harry Boo, Jeiwon Cho, Jeansok J Kim","doi":"10.1016/j.celrep.2025.116081","DOIUrl":"https://doi.org/10.1016/j.celrep.2025.116081","url":null,"abstract":"This study investigates how amyloid pathology influences hippocampal-prefrontal neural dynamics and decision-making in Alzheimer's disease (AD) using 5XFAD mice, a well-established model system characterized by pronounced early amyloid pathology. Utilizing ecologically relevant \"approach food-avoid predator\" foraging tasks, we show that 5XFAD mice exhibit persistent risk-taking behaviors and reduced adaptability to changing threat conditions, indicative of impaired decision-making. Multi-regional neural recordings reveal rigid hippocampal CA1 place cell fields, decreased sharp-wave ripple (SWR) frequencies, and disrupted medial prefrontal-hippocampal connectivity, all of which correspond with deficits in behavioral flexibility during spatial risk scenarios. These findings highlight the critical role of SWR dynamics and corticolimbic circuit integrity in adaptive decision-making, with implications for understanding cognitive decline in AD in naturalistic contexts. By identifying specific neural disruptions underlying risky decision-making deficits, this work provides insights into the neural basis of cognitive dysfunction in AD and suggests potential targets for therapeutic intervention.","PeriodicalId":9798,"journal":{"name":"Cell reports","volume":"44 8","pages":"116081"},"PeriodicalIF":6.9,"publicationDate":"2025-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144759275","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

PFKFB3 activates CAD to enhance de novo pyrimidine synthesis for cell growth. PFKFB3激活CAD，促进细胞生长的从头合成嘧啶。

IF 6.9 1区生物学

Cell reports Pub Date : 2025-07-29 DOI: 10.1016/j.celrep.2025.116071

Qingen Da, Yongfeng Cai, Qian Ma, Qiuhua Yang, Yapeng Cao, Yaqi Zhou, Dingwei Zhao, Zhiping Liu, Jiean Xu, Junming Quan, Liang Zhang, Rui Wang, Xuejun Jiang, Xiao Liu, Kunfu Ouyang, Zhen Han, Jikui Liu, Tao Wang, Chunxiang Zhang, Neal L Weintraub, David J R Fulton, Jun Zhao, Mei Hong, Zigang Li, Yuqing Huo

{"title":"PFKFB3 activates CAD to enhance de novo pyrimidine synthesis for cell growth.","authors":"Qingen Da, Yongfeng Cai, Qian Ma, Qiuhua Yang, Yapeng Cao, Yaqi Zhou, Dingwei Zhao, Zhiping Liu, Jiean Xu, Junming Quan, Liang Zhang, Rui Wang, Xuejun Jiang, Xiao Liu, Kunfu Ouyang, Zhen Han, Jikui Liu, Tao Wang, Chunxiang Zhang, Neal L Weintraub, David J R Fulton, Jun Zhao, Mei Hong, Zigang Li, Yuqing Huo","doi":"10.1016/j.celrep.2025.116071","DOIUrl":"https://doi.org/10.1016/j.celrep.2025.116071","url":null,"abstract":"Aerobic glycolysis, termed the Warburg effect, is one of the aberrant metabolic pathways in highly proliferating cells. Glycolysis provides glycolytic metabolites to support the generation of biomass, such as nucleotides, amino acids, and lipids. Research on the direct interactions between glycolysis and other metabolic pathways is an emerging field that has garnered significant interest. Phosphofructokinase-2/fructose-2,6-bisphosphatase 3 (PFKFB3) activates glycolysis by synthesizing fructose-2,6-bisphosphate (F2,6BP), which allosterically activates the rate-limiting enzyme 6-phosphofructo-1-kinase (PFK-1). In this study, we found that PFKFB3 directly interacts with and regulates the phosphorylation of carbamoyl-phosphate synthetase 2, aspartate transcarbamylase, and dihydroorotase (CAD), the enzyme catalyzing the first three steps of de novo pyrimidine synthesis. PFKFB3 inactivation reduced de novo pyrimidine synthesis, RNA and DNA production, and cell proliferation. Thus, the glycolytic activator PFKFB3 bridges glycolysis with pyrimidine synthesis, unites both glucose metabolism and nucleic acid metabolism, and contributes to cell proliferation under pathological conditions.","PeriodicalId":9798,"journal":{"name":"Cell reports","volume":"44 8","pages":"116071"},"PeriodicalIF":6.9,"publicationDate":"2025-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144759277","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0