Cell Death Discovery最新文献

{"title":"Thapsigargin triggers a non-apoptotic, caspase-independent programmed cell death in basophilic leukaemia cells.","authors":"Philip Steiner, Korollus Melek, Ancuela Andosch, Lena Wiesbauer, Anna Madlmayr, Michelle Duggan, Hubert H Kerschbaum, Susanna Zierler","doi":"10.1038/s41420-025-02602-w","DOIUrl":"10.1038/s41420-025-02602-w","url":null,"abstract":"<p><p>Thapsigargin (TG), a potent inhibitor of the sarco/endoplasmic reticulum Ca²⁺-ATPase (SERCA), is widely used to study intracellular Ca²⁺ homeostasis and has shown-along prodrug derivatives-promise as an anticancer agent. While TG is traditionally considered an inducer of apoptosis, the precise mode of cell death it triggers remains incompletely defined. Here, we investigated the effects of TG on rat basophilic leukaemia (RBL-1) cells using advanced 2D and 3D transmission electron microscopy, confocal laser scanning microscopy, and functional cell death assays. TG treatment led to marked ultrastructural alterations, including pronounced ballooning of the perinuclear space, extensive vacuolization, mitochondrial enlargement and degradation, and structural anomalies of the endoplasmic reticulum. Notably, classical apoptotic features such as nuclear fragmentation, chromatin condensation and apoptotic body formation were absent. Functional assays revealed minimal caspase-3/7 activation and low Annexin V staining, indicating a caspase-independent, non-apoptotic form of programmed cell death (PCD). Morphological and quantitative analyses demonstrated that TG-induced cell death in RBL-1 cells closely resembles autosis, a non-apoptotic, autophagy-dependent PCD characterized by perinuclear space ballooning and increased autophagolysosome formation. These autosis-like features were also observed in TG-treated murine macrophages and human mast cells, suggesting a conserved mechanism across cell types. Digoxin, a Na⁺/K⁺-ATPase inhibitor, partially reversed TG-induced ultrastructural damage, supporting the involvement of Na⁺/K⁺-ATPase in this process. Ca²⁺ imaging confirmed that TG-induced cytosolic Ca²⁺ elevation is primarily driven by ER Ca²⁺ release, with extracellular Ca²⁺ amplifying the response. Our findings establish that TG induces a non-apoptotic, caspase-independent PCD matching autosis, challenging the prevailing view of TG as a classical apoptosis inducer. This insight has important implications for research on intracellular Ca²⁺ homeostasis as well as for the therapeutic exploitation of TG and its derivatives in targeting apoptosis-resistant cancer cells.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":"11 1","pages":"313"},"PeriodicalIF":6.1,"publicationDate":"2025-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12238333/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144590558","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":"Defining the cellular and molecular features of nerve-invaded cancer cells using a newly characterized experimental model.","authors":"Nickson Joseph, Sanskriti Shrestha, Ivanka Sassmannshausen, Sandra Mitzkus, Paulos Chumala, Bhadrapriya Sivakumar, Viswanath Baiju, Shahid Ahmed, Henrike Rees, George S Katselis, Anand Krishnan","doi":"10.1038/s41420-025-02616-4","DOIUrl":"10.1038/s41420-025-02616-4","url":null,"abstract":"<p><p>Perineural invasion (PNI) is the invasion of cancer cells into nerves. Although PNI is a risk factor for cancer recurrence and metastasis, the lack of in vitro experimental models representing natural PNI challenges basic studies and therapeutic screening. In this work, we fully characterized a dorsal root ganglia (DRG)-nerve explant model for PNI and demonstrated the characteristic cellular and molecular features of cancer cells undergoing natural PNI. Briefly, thoracic and lumbar DRGs intactly connected to nerves were co-cultured with breast and prostate cancer cells in a 3D matrix for two weeks. Time-dependent brightfield and fluorescence imaging captured the complex interactions of cancer cells, neurons, axons, and Schwann cells within nerves in the DRG-nerve preparation, demonstrating the natural invasion of cancer cells. Fundamental investigations showed that the autonomic neurotransmitters norepinephrine and acetylcholine significantly promote PNI. We also demonstrated increased survival of PNI cells in response to the treatment with the cytotoxic drug cisplatin. Additionally, we characterized the proteomics profile of PNI cells for future theranostics applications and validated the results using patient breast tumor samples. Overall, this work characterized and established a clinically relevant model for PNI and revealed the cellular crosstalk of PNI cells within nerves. The established model is suitable for fundamental studies and therapeutic screening pertaining to PNI.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":"11 1","pages":"314"},"PeriodicalIF":6.1,"publicationDate":"2025-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12238365/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144590556","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":"Targeting the FOXA1/BMI1 axis to overcome chemoresistance and suppress tumor progression in nasopharyngeal carcinoma.","authors":"Yaping Qin, Mingqing Yang, Yunzhu Cao, Yue Fu, Fan Yang, Xiaoling Zhang, Shengjun Xiao","doi":"10.1038/s41420-025-02595-6","DOIUrl":"10.1038/s41420-025-02595-6","url":null,"abstract":"<p><p>Nasopharyngeal carcinoma (NPC) is a highly aggressive head and neck cancer characterized by a complex etiology and a propensity for metastasis. The current study explores the intricate relationship between Forkhead Box A1 (FOXA1) and B-cell-specific Moloney murine leukemia virus integration site 1 (BMI1) in the cancer progression and chemoresistance of NPC. Our research identified a significant downregulation of FOXA1 in NPC tissues and cell lines, which correlates with advanced clinical stages and poor differentiation, underscoring its potential role as a tumor suppressor. Functional assays demonstrated that the silencing of FOXA1 significantly enhanced the proliferation, migration, and invasive capabilities of NPC cells in vitro. Furthermore, the deficiency of FOXA1 was associated with a diminished sensitivity to cisplatin, as evidenced by increased cell viability, reduced apoptosis, and impaired cell cycle arrest upon drug exposure. Mechanistic studies revealed BMI1 as a critical downstream target of FOXA1. We observed a negative correlation between the expression levels of FOXA1 and BMI1 in NPC tissues. FOXA1 was shown to bind directly to the BMI1 promoter, effectively dampening its transcriptional activity. Rescue experiments indicated that the downregulation of BMI1 could partially reverse the malignant phenotypes induced by FOXA1 silencing, both in vitro and in vivo. Importantly, the knockdown of BMI1 significantly increased the chemosensitivity of FOXA1-depleted NPC cells to cisplatin, effectively counteracting the drug resistance associated with FOXA1 suppression. These findings highlight the pivotal role of FOXA1 in NPC development and progression and suggest that its loss leads to the upregulation of BMI1 and the acquisition of cisplatin resistance. Our study provides novel insights into the molecular mechanisms underlying the malignancy and chemoresistance of NPC and proposes that targeting the FOXA1/BMI1 axis could offer a promising therapeutic strategy for the treatment of this devastating disease.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":"11 1","pages":"311"},"PeriodicalIF":6.1,"publicationDate":"2025-07-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12234731/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144583214","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":"Huaier suppresses lung cancer by simultaneously and independently inhibiting the antioxidant pathway SLC7A11/GPX4 while enhancing ferritinophagy.","authors":"Xingxing Shi, Kun Liu, Yuchang Tian, Xinyi Bi, Junkai Zhang, Fengyi Ma, Wensheng Wei, Tongbiao Zhao","doi":"10.1038/s41420-025-02598-3","DOIUrl":"10.1038/s41420-025-02598-3","url":null,"abstract":"<p><p>Huaier (Trametes Robiniophila Murr), a traditional Chinese medicine, has emerged as a promising therapeutic agent against cancers in clinical settings, yet its underlying mechanisms remain elusive. In this study, we demonstrate that Huaier effectively suppresses lung cancer by inducing ferroptosis. Mechanistically, Huaier simultaneously and independently downregulates the antioxidant pathway SLC7A11/GPX4 and elevates intracellular iron levels through NCOA4-mediated ferritinophagy degradation of FTH1 in lung cancer cells. Both the iron chelator deferoxamine (DFO) and the ferroptosis inhibitor ferrostatin-1 (Fer-1) mitigate Huaier-induced cell death. In both urethane-induced lung tumorigenesis models and cell-derived xenograft (CDX) models, Huaier significantly inhibits tumor progression by inducing ferroptosis, which can be counteracted by SRS16-86. Our study uncovers a novel mechanism by which Huaier induces ferroptosis to suppress lung cancer, underscoring its potential as a therapeutic agent for lung cancer or as part of a combination therapy strategy.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":"11 1","pages":"309"},"PeriodicalIF":6.1,"publicationDate":"2025-07-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12234692/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144583212","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":"Liquid‒liquid phase separation: a potentially fundamental mechanism of sepsis.","authors":"Huiyi Chen, Shunyi Huang, Longcheng Quan, Caiyuan Yu, Yang Zhu, Xiaocong Sun, Yuanli Zhang, Liehua Deng, Feng Chen","doi":"10.1038/s41420-025-02599-2","DOIUrl":"10.1038/s41420-025-02599-2","url":null,"abstract":"<p><p>Sepsis is a life-threatening condition characterized by overactivated inflammation and a dysregulated immune response caused by infection. The predominant mechanism underlying the vulnerability and severity of sepsis has not been fully elucidated. Liquid‒liquid phase separation (LLPS) is a recently discovered, powerful mechanism that drives the formation of membraneless organelles and their biological functions. In particular, emerging evidence indicates that multiple core proteins involved in immune responses, inflammatory signalling, and programmed cell death are organized as protein condensates through LLPS. Here, we present an up-to-date review of the hypothesis that LLPS may underlie the fundamental mechanisms of sepsis, with a focus on the immune system response, changes in inflammatory signalling, and programmed cell death, with the goal of advancing our understanding of the pathological mechanisms of sepsis.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":"11 1","pages":"310"},"PeriodicalIF":6.1,"publicationDate":"2025-07-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12234736/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144583213","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":"Metabolic reprogramming in melanoma therapy.","authors":"Dongliang Shen, Lu Zhang, Shun Li, Liling Tang","doi":"10.1038/s41420-025-02617-3","DOIUrl":"10.1038/s41420-025-02617-3","url":null,"abstract":"<p><p>Melanoma, a deadly and aggressive cancer, exhibits significant metabolic reprogramming that supports energy production, biosynthesis, and tumor progression. This metabolic adaptation drives melanoma growth, proliferation, metastasis, and therapy resistance, highlighting its potential as a promising target for therapeutic intervention. This review focuses on the latest studies elucidating metabolic pathways involved in melanoma progression, therapeutic response, and resistance. Additionally, the potential of targeting metabolic pathways-either alone or in combination with established therapeutic inhibitors-to block disease progression in melanoma is also discussed. Such insights might improve our understanding of metabolic pathways in melanoma development and foster advancements in melanoma therapy.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":"11 1","pages":"308"},"PeriodicalIF":6.1,"publicationDate":"2025-07-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12228840/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144567183","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":"FGF13 prevents age-related hearing loss by protecting spiral ganglion neurons and ribbon synapses from injury.","authors":"Huan Yin, Huan Cao, Jianwang Yang, Tao Liu, Qi Li, Mengxiao Liu, Baoshan Wang","doi":"10.1038/s41420-025-02607-5","DOIUrl":"10.1038/s41420-025-02607-5","url":null,"abstract":"<p><p>Age-related hearing loss (ARHL) is the most common sensorineural hearing loss, and the dysfunction of spiral ganglion neurons (SGNs) and ribbon synapses plays a crucial role in the pathogenesis. The fibroblast growth factor 13 (FGF13) is considered to be associated with neuronal survival and synaptic transmission. However, whether FGF13 is involved in degeneration of SGNs and ribbon synapses, the typical changes of ARHL, is still unknown. Firstly, the expression of FGF13 mRNA and protein, was all dramatically decreased in the SGNs of aged mice, accompanied by impaired SGNs and ribbon synapses. More importantly, specific upregulation of FGF13 in SGNs significantly reduced hearing threshold, improved wave I amplitude, and alleviated loss of SGNs as well as ribbon synapses. Furthermore, the proteomic analysis and verification results suggested that the decrease of FGF13 induced the loss of SGNs and ribbon synapses partly by regulating the ORC1. Taken together, our data revealed that FGF13 might protect SGNs and ribbon synapses by regulating the expression of ORC1, which could provide a new idea and targets for the prevention and treatment of ARHL.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":"11 1","pages":"307"},"PeriodicalIF":6.1,"publicationDate":"2025-07-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12228769/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144567182","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":"Hedgehog pathway, cell cycle, and primary cilium.","authors":"Tenghan Zhuang","doi":"10.1038/s41420-025-02605-7","DOIUrl":"10.1038/s41420-025-02605-7","url":null,"abstract":"<p><p>The Hedgehog (Hh) pathway was initially identified as essential for development and tumorigenesis. In addition to its well-established and indispensable roles within the primary cilium, some components of this pathway have demonstrated more general functions in cell cycle progression. Therefore, this review aims to summarize recent advancements regarding the crosstalk among the Hh pathway, the primary cilium, and the cell cycle, while also highlighting potential issues that may arise in future research.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":"11 1","pages":"302"},"PeriodicalIF":6.1,"publicationDate":"2025-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12229362/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144559324","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":"FL3 mitigates cardiac ischemia-reperfusion injury by promoting mitochondrial fusion to restore calcium homeostasis.","authors":"Zikan Zhong, Yutong Hou, Changzuan Zhou, Jiahui Wang, Longzhe Gao, Xiaoyu Wu, Genqing Zhou, Shaowen Liu, Yingjie Xu, Wen Yang","doi":"10.1038/s41420-025-02575-w","DOIUrl":"10.1038/s41420-025-02575-w","url":null,"abstract":"<p><p>This study aims to investigate the therapeutic potential of Flavagline3 (FL3) in mitigating myocardial ischemia-reperfusion (IR) injury, with a specific focus on its regulatory effects on mitochondrial fusion, mitochondrial-endoplasmic reticulum (ER) interactions, and calcium homeostasis in cardiomyocytes. Using a well-established myocardial IR injury model in mice and primary cardiomyocytes treated with FL3, the study assessed its impact on mitochondrial dynamics and intracellular signaling processes. The results demonstrated that FL3 effectively reduced myocardial apoptosis, infarct size, and cardiac dysfunction caused by IR injury. Mechanistically, FL3 promoted mitochondrial fusion in a mitofusin1 (MFN1)-dependent manner, preserving mitochondrial function under stress conditions and enhancing cellular resilience. Furthermore, FL3 facilitated mitochondrial-ER crosstalk, which played a critical role in modulating intracellular calcium levels by optimizing the transfer of calcium ions between these two organelles. This balanced regulation of mitochondrial dynamics and calcium homeostasis was associated with improved survival and functionality of cardiomyocytes following IR injury. These findings suggest that FL3 exerts robust cardioprotective effects through its ability to promote mitochondrial fusion, enhance mitochondrial-ER interactions, and maintain calcium homeostasis. As a result, FL3 holds promise as a potential therapeutic agent for reducing myocardial damage and dysfunction associated with IR injury, offering valuable insights into novel approaches for cardioprotection.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":"11 1","pages":"304"},"PeriodicalIF":6.1,"publicationDate":"2025-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12229567/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144559323","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":"Demethylzeylasteral suppresses the expression of MESP1 by reducing H3K18la level to inhibit the malignant behaviors of pancreatic cancer.","authors":"Xiaolei Ma, Mengxing Cheng, Yanxin Jia, Kun Zhang, Haocheng Zhang, Di Feng, Wenxiao Xu, Guofen Qiao","doi":"10.1038/s41420-025-02603-9","DOIUrl":"10.1038/s41420-025-02603-9","url":null,"abstract":"<p><p>Glycolysis is a hallmark metabolic pathway in pancreatic cancer (PC). As the end product of glycolysis, lactic acid accumulates significantly in PC. Lactic acid serves as a primary substrate for histone lactylation, leading to an upregulation of histone lactylation levels, which likely contributes to progression of PC. This study reveals novel insights, highlighting that H3K18la levels are elevated in PC tissues and cells. Notably, the natural compound demethylzeylasteral (DML), derived from Tripterygium wilfordii Hook F (TwHF), substantially decreases lactic acid generation in PC cells, subsequently resulting in the downregulation of H3K18la levels and inhibiting the aggressive characteristics of PC cells. To further investigate the underlying mechanisms, we conducted RNA-seq analysis on DML-treated cells and ChIP-seq analyses for H3K18la. For the first time, mesoderm-related factor 1 (MESP1) was identified as a target protein modulated by both DML and H3K18la. DML was shown to repress the expression of MESP1, while sodium lactate (Nala) was found to partially restore its expression levels. Overexpression of MESP1 was linked to the promotion of epithelial-mesenchymal transition (EMT) and apoptosis in PC cells. Furthermore, RNA-seq analyses following MESP1 silencing indicated its significant association with critical physiological processes in PC cells, including the cell cycle, apoptosis, and cell adhesion. Importantly, MESP1 has also been connected to various cancer metabolism pathways, such as MAPK, PI3K-AKT, and carbon metabolism. This research is groundbreaking in demonstrating that DML impedes the malignant behavior of PC cells by downregulating H3K18la levels and diminishing the expression of the oncogene MESP1.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":"11 1","pages":"305"},"PeriodicalIF":6.1,"publicationDate":"2025-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12229608/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144559322","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}