Cell Death Discovery最新文献_第4页

Calcineurin/NFAT signaling in the temporal integration of Ca²⁺ stress in neurodegeneration. 钙调磷酸酶/NFAT信号在神经变性Ca +应激的时间整合中的作用。

IF 10.4 2区生物学

Cell Death Discovery Pub Date : 2026-07-11 DOI: 10.1038/s41420-026-03251-3

Bruna Da Silva Oliveira, Metello Innocenti, Francesca Granucci

{"title":"Calcineurin/NFAT signaling in the temporal integration of Ca²⁺ stress in neurodegeneration.","authors":"Bruna Da Silva Oliveira, Metello Innocenti, Francesca Granucci","doi":"10.1038/s41420-026-03251-3","DOIUrl":"10.1038/s41420-026-03251-3","url":null,"abstract":"The calcineurin (CaN)/nuclear factor of activated T cells (NFAT) signalling axis is a Ca²⁺-responsive pathway that translates intracellular Ca²⁺ signals into long-term transcriptional programmes. Chronic disruption of intracellular Ca²⁺ homoeostasis is a convergent feature of neurodegenerative disorders, particularly Alzheimer's disease (AD) and Parkinson's disease (PD). In these conditions, sustained or repetitive Ca²⁺ elevations promote prolonged activation of the CaN/NFAT pathway, thereby linking Ca²⁺ dysregulation to persistent cellular responses. In this review, we summarise the molecular organisation and regulation of the Ca²⁺/CaN/NFAT pathway and discuss its physiological roles in neurons and glial cells, including synaptic plasticity, neurodevelopment, neurogenesis, and neuroinflammatory responses. We critically examine experimental evidence linking CaN/NFAT signalling to AD and PD, distinguishing direct mechanistic roles from associative and model-dependent findings. Across disease contexts, the CaN/NFAT axis appears to function as a molecular node at which diverse insults, including amyloid-β and tau aggregates, α-synuclein toxicity, mitochondrial dysfunction, and chronic inflammatory cues, converge under conditions of sustained Ca²⁺ dysregulation. We propose that the pathological relevance of CaN/NFAT lies less in pathway activation per se than in its capacity to convert chronic Ca²⁺-dependent stress signals into persistent transcriptional states affecting synaptic integrity, inflammatory tone, and cellular resilience. We conclude by discussing current therapeutic strategies targeting this pathway, their limitations, and the need for temporally and cell-type-specific modulation.","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":" ","pages":""},"PeriodicalIF":10.4,"publicationDate":"2026-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13638984/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148419067","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Intrinsic polyunsaturated fatty acid synthesis capacity dictates ferroptosis sensitivity under restricted arachidonic acid availability. 内在的多不饱和脂肪酸合成能力决定了在限制花生四烯酸可用性下的铁下垂敏感性。

IF 10.4 2区生物学

Cell Death Discovery Pub Date : 2026-07-11 DOI: 10.1038/s41420-026-03240-6

Min Wook Kim, Seo Young Jang, Ji-Yoon Lee, Jong Woo Kim, Woosung Jung, Yeon-Mi You, Jooeun Kim, Kyoung-Jin Oh, Won Kon Kim, Baek-Soo Han, Kwang-Hee Bae, Mi-Young Kim, Geum-Sook Hwang, Eun-Woo Lee

{"title":"Intrinsic polyunsaturated fatty acid synthesis capacity dictates ferroptosis sensitivity under restricted arachidonic acid availability.","authors":"Min Wook Kim, Seo Young Jang, Ji-Yoon Lee, Jong Woo Kim, Woosung Jung, Yeon-Mi You, Jooeun Kim, Kyoung-Jin Oh, Won Kon Kim, Baek-Soo Han, Kwang-Hee Bae, Mi-Young Kim, Geum-Sook Hwang, Eun-Woo Lee","doi":"10.1038/s41420-026-03240-6","DOIUrl":"10.1038/s41420-026-03240-6","url":null,"abstract":"Ferroptosis is an iron-dependent type of regulated cell death driven by lipid peroxidation, in which polyunsaturated fatty acids (PUFAs) in membrane phospholipids serve as key substrates. Here, we identify PUFA biosynthetic capacity as a key determinant of ferroptosis sensitivity under arachidonic acid (AA)-limited conditions. Lipidomic and stable isotope-tracing analyses in human lung adenocarcinoma cell lines revealed that H1299 cells that harbor wild-type KEAP1 and are sensitive to ferroptosis have unexpectedly impaired PUFA biosynthesis and consequently low PUFA levels. Nevertheless, ferroptosis sensitivity in H1299 cells is maintained under normal culture conditions owing to an exogenous supply of AA. Culturing cells in the B27 supplement, which provides only essential fatty acids such as linoleic acid, in the presence of 1% dialyzed FBS reduced AA-containing phospholipids and rendered H1299 cells resistant to ferroptosis. In contrast, A549 cells with a KEAP1 mutation retained ferroptosis sensitivity under B27 conditions, enabled by their endogenous PUFA-synthesizing capacity. Strikingly, pharmacological inhibition of FADS2 or deletion of ELOVL5 in A549 cells phenocopied H1299 cells, conferring resistance under B27-AO conditions that was reversed by AA supplementation. These findings demonstrate that ferroptosis susceptibility is dictated by intrinsic PUFA biosynthetic capacity under AA-limited conditions resembling physiological lipid availability. Therefore, intrinsic PUFA biosynthetic capacity should be considered in ferroptosis-based cancer therapies.","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":" ","pages":""},"PeriodicalIF":10.4,"publicationDate":"2026-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13639061/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148419018","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Single-cell multi-omics deciphers the myofibro-inflammatory program of cancer-associated fibroblasts in triple-negative breast cancer. 单细胞多组学破译三阴性乳腺癌中癌症相关成纤维细胞的肌纤维炎症程序。

IF 10.4 2区生物学

Cell Death Discovery Pub Date : 2026-07-11 DOI: 10.1038/s41420-026-03255-z

Min Li, Jun Lin, Changwei Yang, Jiaqi Yang, Caiqin Mo, Zhishuo Zhang, Anping Liu, Wei Lin, Lin Lin, Wanglong Li, Yiqiu Wang, Xinhuang Hou

{"title":"Single-cell multi-omics deciphers the myofibro-inflammatory program of cancer-associated fibroblasts in triple-negative breast cancer.","authors":"Min Li, Jun Lin, Changwei Yang, Jiaqi Yang, Caiqin Mo, Zhishuo Zhang, Anping Liu, Wei Lin, Lin Lin, Wanglong Li, Yiqiu Wang, Xinhuang Hou","doi":"10.1038/s41420-026-03255-z","DOIUrl":"10.1038/s41420-026-03255-z","url":null,"abstract":"Triple-negative breast cancer (TNBC) is an aggressive subtype associated with poor prognosis and limited therapeutic options, largely due to its unique tumor microenvironment (TME). Cancer-associated fibroblasts (CAFs) critically influence tumor progression and metastasis, yet their functional heterogeneity in TNBC remain poorly understood. An integrated multi-omic analysis was conducted using single-cell RNA sequencing and single-cell ATAC sequencing from TNBC and hormone receptor-positive/HER2-negative (HR + HER2-) breast cancers. The signaling axis was validated critically regulates both TNBC progression and CAF subtype switching. We identified a distinct CAF subpopulation, termed my_iCAFs, characterized by co-expression of myofibroblastic (FAP, ACTA2) and inflammatory markers (CXCL12), significantly enriched within the TNBC TME. My_iCAFs possess elevated activity of pathways involved in epithelial-mesenchymal transition, PI3K/AKT signaling, and pro-inflammatory TNF/NF-κB signaling. Multi-omic integration pinpointed FOSB as a central transcription factor whose expression and chromatin accessibility were selectively enhanced in my_iCAFs, potentially regulated by tumor-derived CXCL8 signaling via syndecan receptors. Also, we found that the FOSB-HES1 axis can effectively activate the transition of CAFs into my_iCAFs. This study reveals a novel FOSB-driven myofibroinflammatory CAF subtype prominently enriched in TNBC, suggesting crucial roles in tumor aggressiveness and highlighting potential therapeutic targets within the stromal compartment of this challenging breast cancer subtype.","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":" ","pages":""},"PeriodicalIF":10.4,"publicationDate":"2026-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13642949/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148419108","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

HMGA proteins in the nervous system: role in brain tumorigenesis and neurodegeneration. 神经系统中的HMGA蛋白：在脑肿瘤发生和神经变性中的作用。

IF 10.4 2区生物学

Cell Death Discovery Pub Date : 2026-07-11 DOI: 10.1038/s41420-026-03242-4

Carolina Canè, Simona Paladino, Andrea Conte, Giovanna Maria Pierantoni

{"title":"HMGA proteins in the nervous system: role in brain tumorigenesis and neurodegeneration.","authors":"Carolina Canè, Simona Paladino, Andrea Conte, Giovanna Maria Pierantoni","doi":"10.1038/s41420-026-03242-4","DOIUrl":"10.1038/s41420-026-03242-4","url":null,"abstract":"High Mobility Group A (HMGA) proteins function as non-histone chromatin-associated architectural regulators that modulate gene transcription by modifying chromatin structure rather than binding DNA in a sequence-specific manner. By altering chromatin conformation, HMGA proteins coordinate complex transcriptional programs essential in both physiological and pathological conditions. This review highlights their emerging roles in the context of the nervous system, brain tumorigenesis, and neurodegeneration. We discuss how HMGA-mediated chromatin remodeling and transcriptional regulation influence neurodevelopmental processes, regulating neural stem cell proliferation, differentiation, and lineage specification. We also highlight evidence linking HMGA dysregulation to malignant transformation and progression of brain tumors, where these proteins support oncogenic transcriptional networks. Finally, we explore their possible involvement in molecular pathways associated with neurodegenerative disorders. By integrating findings from developmental neurobiology, oncology, and neurodegeneration research, we aim to provide a comprehensive overview of HMGA proteins as pivotal regulators of neural homeostasis and highlights their potential as biomarkers and therapeutic targets in neurological diseases.","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":" ","pages":""},"PeriodicalIF":10.4,"publicationDate":"2026-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13638997/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148419096","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

SPINK2 in hematopoiesis and cancer: Biology and clinical implications. 造血和癌症中的SPINK2：生物学和临床意义。

IF 10.4 2区生物学

Cell Death Discovery Pub Date : 2026-07-10 DOI: 10.1038/s41420-026-03206-8

L Deligio, T Loconte, A B Ventura, A Negri, S Ciavarella, G Loseto, L Viggiano, G Castellano, G Fiermonte, G Volpe

{"title":"SPINK2 in hematopoiesis and cancer: Biology and clinical implications.","authors":"L Deligio, T Loconte, A B Ventura, A Negri, S Ciavarella, G Loseto, L Viggiano, G Castellano, G Fiermonte, G Volpe","doi":"10.1038/s41420-026-03206-8","DOIUrl":"10.1038/s41420-026-03206-8","url":null,"abstract":"Serine protease inhibitors are essential regulators of tissue homeostasis, immunity, and cell survival, where they modulate tightly controlled proteolytic signaling networks that influence cell fate and microenvironmental interactions in diverse biological systems. Among them, Kazal-type inhibitors constitute a structurally distinct group defined by a compact, disulfide-rich domain that confers exceptional stability and potent inhibitory activity against a range of serine proteases. SPINK2, a relatively understudied member of this family, has recently gained increasing attention due to its emerging functional roles in haematopoiesis and hematological cancers, as well as for its known function in reproductive biology. Initially identified in the testis as a key regulator of protease-driven germ-cell maturation, SPINK2 expression has since been found in bone marrow-derived hematopoietic stem and progenitor cells (HSPCs), where it contributes to the fine-tuning of protease-mediated signaling, cellular stress responses, and early lineage decisions. Growing evidence now implicates aberrant SPINK2 expression in leukemogenesis, therapy resistance, and bone marrow failure syndromes, highlighting its potential importance as both a mechanistic determinant and a clinically relevant biomarker in hematologic disorders.","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":" ","pages":""},"PeriodicalIF":10.4,"publicationDate":"2026-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13639018/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148419177","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Eosinophil diversity and function: emerging insights into subtypes and therapeutic targets. 嗜酸性粒细胞多样性和功能：对亚型和治疗靶点的新见解。

IF 10.4 2区生物学

Cell Death Discovery Pub Date : 2026-07-10 DOI: 10.1038/s41420-026-03234-4

Faiz Ali Khan, Abhishek Raj, Hizbullah Khan, Mammat Nurahmat, Maimaitijiang Abuduwake, Naibijiang Maitusun, Jingcheng Dong

{"title":"Eosinophil diversity and function: emerging insights into subtypes and therapeutic targets.","authors":"Faiz Ali Khan, Abhishek Raj, Hizbullah Khan, Mammat Nurahmat, Maimaitijiang Abuduwake, Naibijiang Maitusun, Jingcheng Dong","doi":"10.1038/s41420-026-03234-4","DOIUrl":"10.1038/s41420-026-03234-4","url":null,"abstract":"Eosinophils are multifunctional polymorphonuclear granulocytes garnering attention for their roles in disease and maintaining physiological homeostasis. Historically, these immune cells were known to mediate allergic responses and defend against parasitic infections. Recent evidence further links eosinophils to several eosinophil-associated disorders, including eosinophilic esophagitis, eosinophilic granulomatosis with polyangiitis, and hypereosinophilic syndrome; however, their pathogenic contribution appears to be disease-specific and remains incompletely defined in some contexts. The advances in immunology and molecular biology have yielded targeted biologic therapies against eosinophils, significantly improving outcomes for patients with eosinophilic disorders. Concurrently, research reveals that eosinophils are a heterogeneous cell population comprising distinct subtypes that differ in surface protein expression, tissue localization, and functional properties. Specifically, resident eosinophils (rEos) reside in tissues for local maintenance and immune regulation, whereas inflammatory eosinophils (iEos) are rapidly recruited during immune responses to drive inflammation. Initially characterized in murine models, similar eosinophil heterogeneity has since been confirmed in human blood and tissues. Recognizing distinct eosinophil subsets is crucial for understanding their contributions to disease progression. This review highlights recent discoveries in eosinophil diversity and explores therapeutic implications of selectively targeting specific eosinophil subsets in clinical practice.","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":" ","pages":""},"PeriodicalIF":10.4,"publicationDate":"2026-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13639031/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148419004","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Merlin deficiency supports an immunosuppressive milieu in breast cancer. 梅林蛋白缺乏支持乳腺癌的免疫抑制环境。

IF 10.4 2区生物学

Cell Death Discovery Pub Date : 2026-07-09 DOI: 10.1038/s41420-026-03223-7

Mohamed H Elbahoty, Brandon J Metge, Amr R Elhamamsy, Ian Miranda, Melanie Aldridge, Bohan Ning, Hua Guo, Dongquan Chen, Lalita A Shevde

{"title":"Merlin deficiency supports an immunosuppressive milieu in breast cancer.","authors":"Mohamed H Elbahoty, Brandon J Metge, Amr R Elhamamsy, Ian Miranda, Melanie Aldridge, Bohan Ning, Hua Guo, Dongquan Chen, Lalita A Shevde","doi":"10.1038/s41420-026-03223-7","DOIUrl":"10.1038/s41420-026-03223-7","url":null,"abstract":"Despite substantial advances in early detection and therapeutic strategies, breast cancer remains a major cause of cancer-related morbidity and mortality worldwide. Changes in cytoskeletal proteins that typically regulate cellular architecture underpin tumor progression. Merlin, encoded by the NF2 gene and a member of the ezrin-radixin-moesin protein family, functions as a critical cytoskeletal linker protein and a tumor suppressor that governs multiple oncogenic pathways and restricts epithelial-mesenchymal plasticity. While Merlin deficiency alters cellular architecture, the precise impact of a Merlin-deficient breast tumor on remodeling its immune microenvironment remains largely undefined. In this study, we demonstrate that in breast cancer, Merlin deficiency displays attributes consistent with enhanced epithelial-mesenchymal plasticity and enrichment of Hedgehog signaling. In vivo, Merlin-deficient tumors displayed accelerated growth and an immunosuppressive milieu characterized by increased abundance of regulatory T cells and M2-like macrophages. Treatment with Vismodegib, a pharmacological Hedgehog pathway inhibitor, reduced tumor growth of Merlin-deficient basal-like tumors, accompanied by a decrease in tumor-infiltrating regulatory T cells and immunosuppressive M2-like macrophages, and increased recruitment of pro-inflammatory M1-like macrophages. The data present Hedgehog inhibition as a targetable vulnerability of Merlin-deficient basal-like, triple-negative breast cancer.","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":" ","pages":""},"PeriodicalIF":10.4,"publicationDate":"2026-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13633259/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148419050","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

LINC01929 promotes breast cancer progression through a TFRC-associated ferroptosis pathway. LINC01929通过tfrc相关的铁下垂途径促进乳腺癌进展。

IF 10.4 2区生物学

Cell Death Discovery Pub Date : 2026-07-09 DOI: 10.1038/s41420-026-03248-y

Gang Li, Zhijun Yu, Hongmei Xu, Xianglin Sun, Bing Wang, Tianjiao Wei, Yifei Liu, Lisha Ye, Hongmei Qiu, Guohua Wang

{"title":"LINC01929 promotes breast cancer progression through a TFRC-associated ferroptosis pathway.","authors":"Gang Li, Zhijun Yu, Hongmei Xu, Xianglin Sun, Bing Wang, Tianjiao Wei, Yifei Liu, Lisha Ye, Hongmei Qiu, Guohua Wang","doi":"10.1038/s41420-026-03248-y","DOIUrl":"10.1038/s41420-026-03248-y","url":null,"abstract":"Breast cancer (BC) remains the most prevalent malignancy among women worldwide, with persistent challenges such as drug resistance and tumor progression despite significant therapeutic advancements. The roles of ferroptosis and long non-coding RNAs (lncRNAs) in BC are not yet fully elucidated, underscoring the need for novel therapeutic targets. In this study, we investigated the function of LINC01929 in BC through a combination of in vitro and in vivo experiments, bioinformatics analysis, RNA pull-down mass spectrometry, and clinical tissue validation. We found that LINC01929 is significantly overexpressed in BC tissues and is associated with poor patient prognosis. Mechanistically, LINC01929 promoted malignant phenotypes in BC cells and was associated with reduced ferroptosis-related stress, with these effects being at least partly dependent on transferrin receptor (TFRC). Conversely, silencing LINC01929 led to reduced TFRC expression and induced ferroptosis in BC cells. Clinical data further confirmed that elevated TFRC levels correlate with aggressive tumor features and unfavorable outcomes. These findings suggest that targeting LINC01929 to regulate TFRC-mediated ferroptosis could represent a promising therapeutic strategy for BC, positioning both LINC01929 and TFRC as potential biomarkers and therapeutic targets.","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":" ","pages":""},"PeriodicalIF":10.4,"publicationDate":"2026-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13631369/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148419083","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

VK-2019 enhances gemcitabine's antitumor activity in EBV-positive nasopharyngeal carcinoma by upregulating PRODH expression. VK-2019通过上调PRODH表达增强吉西他滨在ebv阳性鼻咽癌中的抗肿瘤活性。

IF 10.4 2区生物学

Cell Death Discovery Pub Date : 2026-07-08 DOI: 10.1038/s41420-026-03247-z

Chengxun Li, Dantong Gu, Yingzhu Li, Li Wang, Hongmeng Yu

引用次数: 0

MFAP2 secreted by TGF-β1-induced cancer-associated fibroblast cells promotes gastric cancer peritoneal metastasis through Src-STAT3-PTK7 axis. TGF-β1诱导的癌相关成纤维细胞分泌MFAP2通过Src-STAT3-PTK7轴促进胃癌腹膜转移。

IF 10.4 2区生物学

Cell Death Discovery Pub Date : 2026-07-08 DOI: 10.1038/s41420-026-03243-3

Yuen Tan, Shulan Sun, Wentao Wang, Yujian Zhang, Zexing Shan, Fan Sun, Yan Zhao, Huimian Xu, Yao Xing, Jianjun Zhang

{"title":"MFAP2 secreted by TGF-β1-induced cancer-associated fibroblast cells promotes gastric cancer peritoneal metastasis through Src-STAT3-PTK7 axis.","authors":"Yuen Tan, Shulan Sun, Wentao Wang, Yujian Zhang, Zexing Shan, Fan Sun, Yan Zhao, Huimian Xu, Yao Xing, Jianjun Zhang","doi":"10.1038/s41420-026-03243-3","DOIUrl":"10.1038/s41420-026-03243-3","url":null,"abstract":"Peritoneal metastasis is the leading risk factor for gastric cancer (GC). However, the mechanism of gastric cancer peritoneal metastasis (GCPM) is still unclear. GCPM depends not only on the \"seeds\" of tumor cells but also on the \"soil\" of the peritoneal microenvironment. This study aimed to analyze the changes in the peritoneal tissue microenvironment of nine patients with early-stage GC, advanced-stage GC, and GCPM using single-cell transcriptome sequencing. It found that the number of microfiber-associated protein 2 (MFAP2)-positive cancer-associated fibroblasts (CAFs) gradually increased with tumor progression and was associated with poor prognosis of GC during GCPM progression. Mechanistically, GC cells secreted transforming growth factor-β1 (TGF-β1) to stimulate the entry of Smad4 into the nucleus. This promoted the transcription of MFAP2 in peritoneal mesothelial cells and led to mesothelial-mesenchymal transition (MMT) of peritoneal mesothelial cells into CAFs, thereby altering the peritoneal microenvironment and facilitating the colonization of GC cells on the peritoneum. Moreover, MFAP2 secreted by CAFs bound to the integrin αVβ3 receptor on the surface of GC cells, activating the Src-STAT3 signaling pathway and upregulating the expression of protein tyrosine kinase 7 (PTK7) in GC cells. PTK7 accumulated intracellular β-catenin and facilitated its nuclear entry, activating transcription of downstream target genes to enhance the invasion and adhesion of GC cells, thereby promoting GCPM progression. Our findings provide insights into how changes in the peritoneal microenvironment promote the peritoneal metastasis of GC, thus providing new molecular targets for personalized treatment and prognostic evaluation in clinical practice.","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":" ","pages":""},"PeriodicalIF":10.4,"publicationDate":"2026-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13631357/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148410670","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0