Cell Death Discovery最新文献

{"title":"IL11 modulates MMP12 expression and cancer cell metastasis via IL11RA/IL6ST-PI3K/Akt/NF-κB pathway in lung cancer.","authors":"Chiang-Wen Lee, Shih-Sen Lin, Tsung-Ming Chang, Zih-Chan Lin, Yao-Chang Chiang, Miao-Ching Chi, Kuo-Ti Peng, Mei-Ling Fang, Ju-Fang Liu","doi":"10.1038/s41420-026-03163-2","DOIUrl":"10.1038/s41420-026-03163-2","url":null,"abstract":"<p><p>Lung cancer is a leading cause of cancer-related mortality, with metastasis significantly reducing patient survival. Interleukin 11 (IL11), a member of the IL-6 cytokine family, has been associated with cancer progression, yet its role in non-small cell lung cancer (NSCLC) metastasis remains unclear. This study analyzed public datasets and demonstrated that IL11 is upregulated in NSCLC and correlates with lymphatic metastasis and poor prognosis. Functional assays revealed that IL11 enhances lung cancer cell migration through upregulation of matrix metalloproteinase 12 (MMP12). Mechanistically, IL11 acts via the IL11 receptor subunit alpha (IL11RA)/ IL6 cytokine family signal transducer (IL6ST) complex to activate the PI3K/Akt/NF-κB signaling pathway, which in turn drives MMP12 expression and promotes metastatic behavior. Notably, the clinically approved selective estrogen receptor modulator bazedoxifene effectively inhibited IL11-induced signaling, reduced MMP12 levels, and suppressed cancer cell migration in vitro. In an orthotopic lung cancer mouse model, IL11 knockdown significantly reduced tumor growth and intrapulmonary spread, accompanied by decreased IL11, MMP12, and phosphorylated NF-κB p65 levels in lung tissues. These findings uncover a novel IL11-driven pathway contributing to metastatic behavior in NSCLC and identify the IL11/IL11RA/IL6ST axis as a potential therapeutic target. Schematic representation of bazedoxifene-mediated suppression of IL11-induced pro-metastatic signaling in lung cancer. Non-small cell lung cancer (NSCLC) cells secrete IL11, which binds to the IL11RA/IL6ST receptor complex and activates the PI3K/Akt signaling pathway. This activation enhances NF-κB transcriptional activity, leading to upregulated MMP12 expression and promoting lung cancer cell migration. Notably, bazedoxifene effectively blocks IL11-induced PI3K/Akt activation, thereby suppressing NF-κB signaling and reducing MMP12 expression, which ultimately attenuates NSCLC metastasis.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":" ","pages":""},"PeriodicalIF":10.4,"publicationDate":"2026-06-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13478155/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148223518","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}

{"title":"PHGDH loss promotes hypoxia tolerance through glycolytic reprogramming and enhanced HIF-1 activity.","authors":"Eduard Petrosyan, Louise A W Martin, Isabelle Legge, John Walsby-Tickle, Adam C Sedgwick, Mark A Hill, James S O McCullagh, Monica M Olcina, Ester M Hammond","doi":"10.1038/s41420-026-03194-9","DOIUrl":"10.1038/s41420-026-03194-9","url":null,"abstract":"<p><p>Radiotherapy is widely used in the treatment of lung cancer; a number of intrinsic and extrinsic mechanisms of resistance exist, including hypoxia. Targeting metabolic pathways that support redox homeostasis has been proposed as a strategy to enhance radiosensitivity. The serine synthesis pathway enzyme, phosphoglycerate dehydrogenase (PHGDH), has been implicated in resistance to several anticancer therapies; however, its role in radiotherapy response is poorly defined. We show that PHGDH expression positively correlates with established hypoxia gene expression signatures in lung adenocarcinoma and squamous cell carcinoma patient datasets and is induced under hypoxia (<0.1% O₂) in lung cancer cell lines. Hypoxic induction of PHGDH appears mediated by both HIF-1 and PERK signalling, linking PHGDH regulation to hypoxia and the unfolded protein response. Using CRISPR-Cas9 PHGDH knockout models, we demonstrate that loss of PHGDH does not enhance radiosensitivity in normoxia or hypoxia when extracellular serine and glycine are available at physiological or supraphysiological concentrations. Radiosensitisation is observed only under complete serine/glycine deprivation. Unexpectedly, PHGDH loss confers increased tolerance to hypoxic stress, associated with elevated glycolytic flux, increased lactate production, accelerated HIF-1α stabilisation and enhanced expression of hypoxia-inducible genes. Overall, these data indicate that targeting PHGDH alone is unlikely to impact radioresistance in lung cancer under physiologically relevant nutrient conditions and may instead promote metabolic adaptation to hypoxia. This highlights the importance of microenvironmental context when evaluating metabolic targets for combination with radiotherapy.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":" ","pages":""},"PeriodicalIF":10.4,"publicationDate":"2026-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13478179/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148216666","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}

{"title":"Mechanistic analysis of MLKL-driven cell survival.","authors":"Peijia Jiang, Xiaoyang Liu, Mauricio J Reginato, Kirill V Rosen","doi":"10.1038/s41420-026-03187-8","DOIUrl":"10.1038/s41420-026-03187-8","url":null,"abstract":"<p><p>MLKL pseudokinase is a critical executioner of necroptotic cell death. MLKL drives necroptosis by forming pores in the cell membrane. A growing body of data indicates that, in addition to this well-established role, MLKL can promote cell survival in certain contexts. Moreover, pharmacological or genetic MLKL inhibition was shown to suppress in vivo growth of several tumor types. It was found that MLKL protects cancer cells from various cell death-inducing stimuli by promoting autophagy or preserving the mitochondrial function of the cells. It was proposed that both of these MLKL effects prevent parthanatos, a cell death type mediated by hyperactivation of PARP1 and subsequent PARP1-dependent chromosomal DNA degradation. In addition, MLKL was found to protect tumor cells from the death receptor-induced demise and trigger the secretion of the growth-promoting cytokines by the cells. Notably, MLKL-deficient mice are healthy, while pharmacological MLKL inhibitors are not significantly toxic to mice. Hence, targeting MLKL in vivo to block MLKL-dependent cancer cell survival is feasible. The mechanisms of the pro-survival MLKL effects is the subject of this review.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":" ","pages":""},"PeriodicalIF":10.4,"publicationDate":"2026-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13478468/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148216683","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}

{"title":"Characterization of programmed cell death pathways activated in Mycobacterium tuberculosis-infected human macrophages.","authors":"Guanchao Ding, Jacques Augenstreich, Anushka Poddar, Akshaya Ganesh, Liron David, Ravin Fisher, Volker Briken","doi":"10.1038/s41420-026-03156-1","DOIUrl":"10.1038/s41420-026-03156-1","url":null,"abstract":"<p><p>Mycobacterium tuberculosis (Mtb) primarily infects human lung macrophages, which serve as its major replication niche. Mtb can manipulate host macrophage cell death pathways to its advantage by inhibiting apoptosis and inducing necrotic cell death. However, the specific necrotic cell death pathway activated in human macrophages after Mtb infection remains unclear. Here, we used the THP-1 cell line and primary human monocyte-derived macrophage (hMDM) to analyze multiple programmed cell death pathways during days 1-3 after Mtb infection. Confocal microscopic analysis demonstrates that Mtb-infected THP-1 cells or hMDMs rarely exhibited apoptosis. Immunoblotting shows that Mtb induces significant CASP3 and GSDME activation in THP-1 cells, but not in hMDMs. We show that Mtb, in THP-1 cells but not hMDM, induces a significant increase in GSDMD cleavage, a hallmark of pyroptosis. MLKL phosphorylation was not observed in THP-1 cells or hMDMs during Mtb infections, indicating an absence of necroptosis. No changes in ferroptosis markers such as GPX4 expression or lipid peroxidation levels were detected. Time-lapse live-cell imaging revealed no lysosomal membrane permeabilization prior to plasma membrane rupture (PMR). However, we observed DNA release from Mtb-infected THP-1 cells and hMDMs after PMR. The DNA released from THP-1 cells exhibits low levels of myeloperoxidase and histone H3 citrullination. High-resolution confocal imaging shows that Mtb is associated with the released DNA. We demonstrate that pyroptosis induction in THP-1 cells is dispensable for the DNA release and cell death induction. In conclusion, our results reveal that Mtb-triggered cell death in hMDMs bypasses canonical cell death pathways like apoptosis, pyroptosis, necroptosis, and ferroptosis. Instead, cell death in both THP-1 cells and hMDMs correlates with DNA release, potentially similar to NETosis in neutrophils.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":" ","pages":""},"PeriodicalIF":10.4,"publicationDate":"2026-06-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13470034/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148204173","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}

{"title":"Novel truncating Desmin mutation Arg150Stop disrupts structural integrity and cellular homeostasis by formation of persistent aggregate-like structure.","authors":"Sukanya Mitra, Trisha Ghosh, Arun Kumar Mishra, Shamita Sanga, Sai Gayathri R, Mahua Maulik, Moulinath Acharya","doi":"10.1038/s41420-026-03184-x","DOIUrl":"10.1038/s41420-026-03184-x","url":null,"abstract":"<p><p>Desminopathies are a heterogeneous group of myofibrillar myopathies defined by the presence of desmin-positive aggregates that compromise cytoskeletal integrity in skeletal and cardiac muscle. Although desmin knockout models and several truncating mutations typically result in a functional null phenotype without inclusion body formation, the molecular consequences of specific stop-gain variants remain poorly understood. In this study, we investigated the pathogenic mechanism of a novel Desmin (DES) nonsense mutation, NM_001927.4:c.448 C > T; p.(Arg150Stop), previously identified in an Indian patient with congenital myopathy. This premature stop codon lies within the Linker 1 A domain and is predicted to generate a truncated protein lacking the C-terminal tail. To delineate its functional consequences, we used two complementary experimental approaches: transient overexpression of the Arg150Stop mutant in skeletal and cardiac myocytes, and a CRISPR/Cas9-engineered homozygous Arg150stop cardiomyocyte line (Des^tr-CRISPR). Both models consistently revealed the formation of persistent aggregate-like structures, in striking contrast to desmin knockout systems that do not generate inclusions. These aggregate-like structures disrupted actin filament organization, impaired filament bundling, and induced organelle mislocalization. Biochemical analysis indicated that the aggregates were resistant to proteasomal degradation, yet they were partially cleared by autophagy, underscoring a role for protein quality control pathways in modulating disease severity. Importantly, the Des^tr-CRISPR line demonstrated aggregate-driven pathology at endogenous levels, confirming that this mutation acts through a toxic gain-of-function mechanism rather than simple loss of desmin function. Our findings establish the Arg150Stop variant as a mechanistically distinct truncating mutation that generates aggregation-prone protein rather than a null state. By reproducing hallmark features of desminopathy in a physiologically relevant human cell models, this work not only broadens the known pathogenic spectrum of DES variants but also highlights aggregate formation as a central driver of cellular dysfunction and a promising therapeutic target in desminopathies.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":" ","pages":""},"PeriodicalIF":10.4,"publicationDate":"2026-06-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13458698/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148175416","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}

{"title":"Identification of tumor-promoting functions of the Homeobox family transcription factor MSX1 in cervical cancer.","authors":"Paulina Brücker, Svenja Horn, Shaishavi Jansari, Marianna Kombou, Simon Eppich, Udo Jeschke, Samy Hakroush, Stefan Küffer, Sonja Fritzsche, Florian Wegwitz, Julia Gallwas","doi":"10.1038/s41420-026-03191-y","DOIUrl":"10.1038/s41420-026-03191-y","url":null,"abstract":"<p><p>Cervical cancer (CC) remains a leading cause of cancer-related mortality among women, particularly in underdeveloped or developing countries lacking adequate screening programs. Despite being highly preventable through HPV vaccinations and screening tests, and highly treatable when detected early, CC continues to pose a significant health burden. MSX1, a transcription factor of the homeobox family, plays an important role in the development and differentiation of tissues, including the gynecological tract. Since MSX1 has been identified as both a tumor suppressor and an oncogene in tumorigenesis, but its function in CC remains elusive to date, the present study aims to elucidate the role of MSX1 in CC and its precancerous stages. Our results demonstrate that MSX1 acts as a tumor-promoting factor in CC. While normal squamous epithelium of the cervix is negative for MSX1, we observed de novo expression of MSX1 in precancerous lesions. We found that MSX1 expression enhances the clonogenic and migratory capacities of cervical cancer cell lines. Mechanistic insights revealed an MSX1-dependent induction of the epithelial-to-mesenchymal transition (EMT), a process highly correlated with cancer development and progression. CUT&RUN sequencing data identified enriched signaling of the cytoskeletal modulators RHO/RAC/CDC42 in MSX1-expressing cells, potentially mediated by MSX1. Additionally, FOS, a downstream effector of RHO, was found as a key factor contributing to CC aggressiveness. Interference with both RHO-signaling and FOS-mediated regulation completely reversed the aggressive phenotype of MSX1-expressing cells. In conclusion, our findings suggest that MSX1 plays a crucial role in cancer-related signaling pathways and may have implications for the development of therapeutic approaches in cervical cancer.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":"12 1","pages":""},"PeriodicalIF":10.4,"publicationDate":"2026-06-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13241535/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148175466","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}

{"title":"An electrophysiological and proteomics roadmap for human induced glutamatergic neurons: fine-tuning of culture conditions for pathophysiological studies.","authors":"Martina Servetti, Giulia Parodi, Martino Caramia, Ennio Nano, Martina Bartolucci, Antonella Marte, Giacomo Mazzoni, Simone Giubbolini, Farah Diab, Andrea Petretto, Pierluigi Valente, Sergio Martinoia, Simona Baldassari, Anna Fassio, Fabio Benfenati, Anna Corradi, Bruno Sterlini","doi":"10.1038/s41420-026-03185-w","DOIUrl":"10.1038/s41420-026-03185-w","url":null,"abstract":"<p><p>Induced glutamatergic neurons (iGluNeurons) generated by Neurogenin-2 (NGN2) overexpression in human pluripotent stem cells are a powerful model for studying human neuronal maturation and function; however, NGN2-based protocols still lack standardized culture conditions that critically affect neuronal development and function. Three key factors have been identified by previous literature, namely the composition of extracellular matrix coating, the initial plating density, and the choice of culture medium, but the differential effects of their combination have not been thoroughly analyzed. Here, we investigated the combinatorial effects of these three variables, testing eight distinct culture conditions resulting from the combinations of two coatings (poly-L-ornithine and polyethyleneimine), two media (BrainPhys and Neurobasal), and two cell densities (4800 and 1200 cells/mm²). We assessed electrophysiological properties at the single-cell and network levels, characterized morphofunctional and proteomic features across multiple developmental stages. Electrophysiological data indicate that medium composition and plating density, rather than substrate coating, determine neuronal maturation dynamics, with BrainPhys and high density promoting rapid but transient maturation while Neurobasal and low density supporting gradual and sustained network development. Morphofunctional analyzes of synapses and the axon initial segment, together with neuronal maturation markers, support an early BrainPhys-driven acceleration of development that is later exceeded by Neurobasal. To enable accurate proteome profiling of the iGluNeuron system-comprising human neurons and rat astrocytes-we developed a robust taxonomic filtering algorithm that selectively identifies human-specific proteins. This approach confirmed the presence of a conserved core of NGN2-driven differentiation pathways across all settings, in addition to condition-specific signatures. Finally, in the optimal conditions identified through our experimental analyzes, robust spontaneous and evoked synaptic activity was observed. These results provide a framework for optimizing iGluNeuron cultures, balancing rapid maturation and long-term functional stability, and establishing a benchmark for human neuronal models in disease research and drug screening.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":" ","pages":""},"PeriodicalIF":10.4,"publicationDate":"2026-06-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13458295/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148175418","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}

{"title":"ATP binding to lysozyme and superfolder GFP amyloid fibrils induces aggregate remodeling and attenuates their cytotoxicity.","authors":"Olga V Stepanenko, Maksim I Sulatsky, Kristina G Gridasova, Ekaterina V Mikhailova, Anna I Sulatskaya, Olesya V Stepanenko","doi":"10.1038/s41420-026-03186-9","DOIUrl":"10.1038/s41420-026-03186-9","url":null,"abstract":"<p><p>The pathogenesis of neurodegenerative diseases such as Alzheimer's and Parkinson's, systemic and local amyloidoses is closely associated with amyloid fibril accumulation. Dysregulation of energy metabolism and a decline in the level of adenosine triphosphate (ATP), a key intracellular energy source and extracellular signaling molecule, contribute to the development of these pathologies. Despite the well-established role of ATP as a biological hydrotrope that prevents the initial aggregation of proteins, the impact of this nucleotide on the structure and properties of pre-formed (mature) amyloids is still poorly understood. In this study, we showed the ability of ATP to bind with affinity in the low-to-mid micromolar range to mature amyloids of lysozyme, which associated with hereditary lysozyme amyloidosis, and superfolder GFP, as model objects with unique properties, demonstrating a significant increase in the number of binding sites compared to native proteins. We demonstrated that this interaction induces declustering of both aggregate types, accompanied by fibril disordering specific to certain amyloidogenic proteins. Importantly, ATP-mediated fibril remodeling resulted in a significant reduction in their toxicity to mammalian cell lines, as well as a decrease in the aggregate resistance to chemical and thermal degradation. The obtained results reveal the complex nature of ATP's effects: while acting as an endogenous amyloid detoxification factor, it is also susceptible to sequestration in amyloid deposits due to its affinity in the low-to-mid micromolar range. Amyloid-associated ATP sequestration may lead to nucleotide deficiency and aggravation of amyloidosis.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":" ","pages":""},"PeriodicalIF":10.4,"publicationDate":"2026-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13451496/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148161875","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}

{"title":"Dynamic calcium-potassium balancing by KCNMA1 preserves the epithelial/mesenchymal hybrid state and modulates therapy response in ovarian cancer.","authors":"Tereza Buchtova, Jirina Bartkova, Tatsuro Yamamoto, Marie Lund Bay, Allan Jensen, Susanne Krüger Kjær, Tuula Kallunki, Jiri Bartek, Robert Strauss","doi":"10.1038/s41420-026-03189-6","DOIUrl":"10.1038/s41420-026-03189-6","url":null,"abstract":"<p><p>Tumor cell plasticity and stemness fuel treatment resistance and cancer evolution into often incurable, metastatic terminal disease. To better understand these fundamental aspects of tumorigenesis, here we examine a potential role of KCNMA1, a calcium-activated potassium channel that impacts cell (patho)physiology through membrane functions, in regulating ovarian cancer cell behavior, including plasticity, proliferation, mobility, and response to treatment. Pharmacological activation of KCNMA1 promoted differentiation, while channel blocking induced dedifferentiation and enhanced dissemination potential. Cyclical activation and inhibition potentiated the epithelial/mesenchymal hybrid cell state prone to stemness. KCNMA1 overexpression combined with low-dose channel blockade supported three-dimensional tumor growth. Mechanistically, we found that the balance between cytosolic calcium and potassium, in addition to their absolute levels, governed the observed changes. Our findings support a model in which KCNMA1-mediated regulation of potassium buffers fluctuating calcium signals that drive phenotypic plasticity, thereby stabilizing the epithelial/mesenchymal hybrid state. In addition, KCNMA1 modulation sensitized ovarian cancer cells to standard-of-care chemotherapeutics. Together, this work provides new insights into the role of KCNMA1 and calcium/potassium homeostasis in ovarian cancer cell adaptability, with implications for treatment.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":" ","pages":""},"PeriodicalIF":10.4,"publicationDate":"2026-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13454608/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148161905","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}

{"title":"Apatinib inhibits synovial sarcoma progression and angiogenesis via VEGFR2-mediated AKT/FOXO3A and ERK1/2/FOXM1 signaling pathways.","authors":"Ruijie Liu, Fengzhen Zhang, Kai Shi, Wenhao Wang, Xuewen Li, Shaobo Lu, Bowen Chen, Dongjin Wu, Changliang Peng","doi":"10.1038/s41420-026-03188-7","DOIUrl":"10.1038/s41420-026-03188-7","url":null,"abstract":"<p><p>Synovial sarcoma (SS) is a highly aggressive soft-tissue malignancy with limited therapeutic options for advanced disease. Here, we report that apatinib, a selective VEGFR2 tyrosine kinase inhibitor, exerts potent antitumor and anti-angiogenic activity in SS. In SS cell lines, apatinib reduced cell viability, induced G1 phase arrest, and triggered both apoptosis and autophagy. Apatinib further suppressed the metastatic phenotype by inhibiting cell migration, invasion, and EMT, while simultaneously reducing VEGF expression and impairing endothelial tube formation. Mechanistically, apatinib suppressed the VEGFR2/AKT/FOXO3A and ERK1/2/FOXM1 axes in tumor cells, thereby restraining proliferation and angiogenic signaling, and directly impaired endothelial function via the VEGFR2/AKT/eNOS/NO pathway in HUVECs. In vivo, apatinib markedly suppressed xenograft tumor growth and modulated the corresponding signaling pathways. Collectively, our findings identify apatinib as a promising therapeutic agent that disrupts interconnected survival and angiogenic networks in SS.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":" ","pages":""},"PeriodicalIF":10.4,"publicationDate":"2026-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13442848/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148155472","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}