Cell Death Discovery最新文献

{"title":"Enhancing venetoclax efficacy in leukemia through association with HDAC inhibitors.","authors":"Jorge Antonio Elias Godoy Carlos, Mauricio Temotheo Tavares, Keli Lima, Larissa Costa de Almeida, Karoline de Barros Waitman, Leticia Veras Costa-Lotufo, Roberto Parise-Filho, João Agostinho Machado-Neto","doi":"10.1038/s41420-025-02446-4","DOIUrl":"10.1038/s41420-025-02446-4","url":null,"abstract":"<p><p>Epigenetic modifications significantly influence gene expression and play crucial roles in various biological processes, including carcinogenesis. This study investigates the effects of novel purine-benzohydroxamate compounds, particularly 4 f, as hybrid kinase/histone deacetylase (HDAC) inhibitors in hematological malignancies, focusing on acute myeloid leukemia (AML). Our results demonstrate that these compounds selectively reduce cell viability in blood cancer cells, with inhibitory concentration values indicating higher potency against neoplastic cells compared to normal leukocytes. Mechanistically, 4 f induces apoptosis and cell cycle arrest, promoting differentiation in leukemia cells, while effectively inhibiting HDAC activity. Furthermore, 4 f enhances the therapeutic efficacy of venetoclax, a BCL2 inhibitor, in AML models sensitive and resistant to this drug. The combination treatment significantly increases apoptosis and reduces cell viability, suggesting a synergistic effect that may overcome drug resistance. This study provides valuable insights into the potential of HDAC inhibitors, particularly 4 f, as a promising therapeutic strategy for treating resistant hematological malignancies. Our findings underscore the importance of further exploring hybrid kinase/HDAC inhibitors in combination therapies to improve outcomes in patients with acute leukemias and other hematological malignancies.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":"11 1","pages":"147"},"PeriodicalIF":6.1,"publicationDate":"2025-04-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11972356/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143787977","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":"Navigating the future of gastric cancer treatment: a review on the impact of antibody-drug conjugates.","authors":"Qingling Yin, Yanlong Zhang, Xueqing Xie, Meijun Hou, Xunsheng Chen, Jie Ding","doi":"10.1038/s41420-025-02429-5","DOIUrl":"10.1038/s41420-025-02429-5","url":null,"abstract":"<p><p>Gastric cancer, marked by its high incidence and poor prognosis, demands the urgent development of novel and effective treatment strategies, especially for patients ineligible for surgery or those who have had limited success with chemotherapy, radiotherapy and targeted therapies. Recently, antibody-drug conjugates (ADCs) have become a key area of investigation due to their high specificity and potent antitumor effects. These therapies combine monoclonal antibodies, designed to bind to tumor-specific antigens, with cytotoxic agents that selectively target and destroy malignant cells. ADCs have generated significant interest in clinical trials as a promising approach to improve both treatment efficacy and patient outcomes in gastric cancer. However, their clinical application is not without challenges and limitations that must be addressed. This review discusses the recent progress in the use of ADCs for gastric cancer treatment.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":"11 1","pages":"144"},"PeriodicalIF":6.1,"publicationDate":"2025-04-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11972320/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143787984","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":"Inhibition of CHI3L1 attenuates excessive autophagy in intestinal epithelial cells to reduce the severity of necrotizing enterocolitis.","authors":"Yihui Li, Wenqiang Sun, Xinyun Jin, Huiwen Li, Xue Liu, Jingtao Bian, Xueping Zhu","doi":"10.1038/s41420-025-02443-7","DOIUrl":"10.1038/s41420-025-02443-7","url":null,"abstract":"<p><p>Neonatal necrotizing enterocolitis (NEC) is a devastating intestinal disease that primarily affects preterm infants. Unfortunately, no specific treatment for NEC is currently available, making it crucial to further investigate its underlying mechanisms. In this study, we aimed to identify the key target gene, CHI3L1, which was significantly upregulated in the intestinal tissues of both affected children and model mice from the GEO database. CHI3L1 is known to play important roles in inflammatory and immune responses, as well as in tissue damage and repair, all of which are closely associated with the development of NEC. We conducted validations at both the cellular and animal levels, demonstrating that the inhibition or knockdown of CHI3L1 significantly reduced the severity of NEC. Mechanistic investigations revealed that the knockdown of CHI3L1 inhibited the PI3K-Akt-FoxO1 signalling pathway, alleviating excessive autophagy in intestinal epithelial cells and subsequently reducing injury and inflammatory responses. Clinical studies have revealed that elevated serum CHI3L1 expression in paediatric patients is associated with both the occurrence and severity of necrotising enterocolitis NEC, demonstrating positive correlations with the Duke Abdominal Assessment Scale (DAAS), C-reactive protein (CRP), procalcitonin (PCT), red cell distribution width (RDW), and lactate dehydrogenase (LDH) levels. In conclusion, our findings confirmed a close relationship between CHI3L1 and the occurrence and severity of NEC, suggesting that it may mitigate inflammatory responses and tissue damage by alleviating excessive autophagy in intestinal epithelial cells. Therefore, targeting CHI3L1 may be an effective strategy to combat NEC.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":"11 1","pages":"145"},"PeriodicalIF":6.1,"publicationDate":"2025-04-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11972288/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143787979","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":"Integrative insights into the role of CAV1 in ketogenic diet and ferroptosis in pancreatic cancer.","authors":"Xue Liang, Ruofei Tian, Ting Li, Hao Wang, Yifei Qin, Meirui Qian, Jing Fan, Dan Wang, Hong-Yong Cui, Jianli Jiang","doi":"10.1038/s41420-025-02421-z","DOIUrl":"10.1038/s41420-025-02421-z","url":null,"abstract":"<p><p>Pancreatic cancer exhibits high mortality rates with limited therapeutic options. Emerging evidence suggests that the ketogenic diet may act as adjuvant therapy by triggering ferroptosis in cancer cells, though the underlying molecular mechanisms remain unclear. This study aims to investigate the molecular mechanisms linking ketogenic metabolism and ferroptosis, with an emphasis on key regulatory proteins. We demonstrated that pancreatic adenocarcinoma (PAAD) tissues significantly enhanced ketogenic and ferroptosis phenotypes compared to normal tissues, both correlating with poorer patient prognosis. These phenotypes showed strong interdependence mediated by CAV1. In the pancreatic tumor microenvironment, CAV1 was predominantly expressed in tumor cells. Through in vitro cell experiments, we clarified that Na-OHB downregulated CAV1 expression in pancreatic cancer cells, inhibiting the transcription of the CAV1/AMPK/NRF2 downstream ferroptosis-protective genes SLC7A11 and SLC40A1. Additionally, we demonstrated the interaction between CAV1 and SLC7A11 molecules; when CAV1 was downregulated, it affected the stability of SLC7A11, leading to the ubiquitination and degradation of the translated SLC7A11 protein. Through these dual mechanisms, Na-OHB caused Fe²⁺ overload, lipid peroxidation accumulation, and oxidative stress in pancreatic cancer cells, ultimately triggering ferroptosis. In ketogenic diet-fed tumor-bearing mouse models, we also observed a significant increase in lipid peroxidation and other related biomarkers, while CAV1 and SLC7A11 levels were markedly decreased compared to the normal diet group. Our findings identify CAV1 as a pivotal molecular link between ketogenic metabolism and ferroptosis in pancreatic cancer. The multi-level regulatory axis involving CAV1-mediated transcriptional regulation and post-translational modifications provides mechanistic insights into ketogenic diet-induced ferroptosis, suggesting potential therapeutic targets for pancreatic cancer adjuvant treatment.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":"11 1","pages":"139"},"PeriodicalIF":6.1,"publicationDate":"2025-04-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11968908/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143779047","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":"Roles of the gut microbiota in hepatocellular carcinoma: from the gut dysbiosis to the intratumoral microbiota.","authors":"Yiqin Wang, Yongqiang Li, Yong Lin, Chuangyu Cao, Dongcheng Chen, Xianguang Huang, Canhua Li, Haoming Xu, Huasheng Lai, Huiting Chen, Yongjian Zhou","doi":"10.1038/s41420-025-02413-z","DOIUrl":"10.1038/s41420-025-02413-z","url":null,"abstract":"<p><p>Hepatocellular carcinoma (HCC) is closely linked to alterations in the gut microbiota. This dysbiosis is characterized by significant changes in the microbial population, which correlate with the progression of HCC. Gut dysbiosis ultimately promotes HCC development in several ways: it damages the integrity of the gut-vascular barrier (GVB), alters the tumor microenvironment (TME), and even affects the intratumoral microbiota. Subsequently, intratumoral microbiota present a characteristic profile and play an essential role in HCC progression mainly by causing DNA damage, mediating tumor-related signaling pathways, altering the TME, promoting HCC metastasis, or through other mechanisms. Both gut microbiota and intratumoral microbiota have dual effects on HCC progression; a comprehensive understanding of their complex biological roles will provide a theoretical foundation for potential clinical applications in HCC treatment.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":"11 1","pages":"140"},"PeriodicalIF":6.1,"publicationDate":"2025-04-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11971373/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143787988","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":"A hypoxia research-driven path led to identifying neuroprotection mediators: an interview with Dr. Nicolas G. Bazan.","authors":"Nicolas G Bazan","doi":"10.1038/s41420-025-02436-6","DOIUrl":"10.1038/s41420-025-02436-6","url":null,"abstract":"","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":"11 1","pages":"141"},"PeriodicalIF":6.1,"publicationDate":"2025-04-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11971240/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143787976","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":"Navigating thyroid cancer complexity: the emerging role of EV-derived non-coding RNAs.","authors":"Meng Jia, Jiawen Liang, Lu Gao, Na Wei, Ye Qin, Qianqian Li, Xintao Wang, Jian Zheng, Hao Wang, Jie Wang, Shuo Wang, Xiubo Lu","doi":"10.1038/s41420-025-02411-1","DOIUrl":"10.1038/s41420-025-02411-1","url":null,"abstract":"<p><p>Thyroid cancer (TC), which arises from the epithelial cells of the thyroid gland, is experiencing a significant increase in incidence globally. TC encompasses various subtypes, including papillary, follicular, medullary, and anaplastic thyroid cancers, each with distinct pathological and clinical features. Extracellular vesicles (EVs), are naturally occurring and nanosized lipid bilayers, and can be secreted by almost all cell types. EVs, comprising microvesicles and exosomes, are pivotal in mediating intercellular communication within the tumor microenvironment. Notably, EVs possess unique properties such as stability in circulation and the ability to traverse biological barriers, enhancing their role as carriers of molecular information. EVs carry non-coding RNAs (ncRNAs), including miRNAs, lncRNAs, and circRNAs, which are crucial regulators of gene expression. Recent studies have highlighted the significant role of EV-derived ncRNAs in influencing thyroid cancer progression, metastasis, and immune modulation by mediating intercellular communication within the tumor microenvironment. The expression of EV-derived ncRNAs varies across different stages of thyroid cancer, reflecting potential as biomarkers for diagnosis and targets for therapy. This review delves into the multifaceted roles of EV-ncRNAs in thyroid cancer, emphasizing their impact on tumor growth, metastatic potential, and immune interactions, while also exploring their promising applications in early diagnosis and targeted treatment strategies. Understanding these dynamics is essential for developing innovative interventions to improve patient outcomes in thyroid cancer.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":"11 1","pages":"142"},"PeriodicalIF":6.1,"publicationDate":"2025-04-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11971377/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143787985","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":"Non-immune targeting of CXCR3 compromises mitochondrial function and suppresses tumor growth in glioblastoma.","authors":"Travis Yui Hei Chan, Bo Chen, Wanjun Tang, Henry Hei Chan, Yogesh K H Wong, Ethan C L Wong, Junbo Liao, Anson Cho-Kiu Ng, Jenny Sum Yee Wong, Gilberto Ka-Kit Leung, Karrie M Kiang","doi":"10.1038/s41420-025-02449-1","DOIUrl":"10.1038/s41420-025-02449-1","url":null,"abstract":"<p><p>The chemokine receptor CXCR3 is traditionally recognized for its role in immune cell trafficking. However, emerging evidence suggests that its functions may extend beyond the immune system, particularly in cancer, where its roles remain to be elucidated. In this study, we demonstrated that CXCR3 expression correlates with glioblastoma (GBM) grading, with CXCR3-A isoform being associated with poorer patient prognosis compared to CXCR3-B. Ablation of both CXCR3 isoforms significantly impaired GBM cell proliferation, migration, and tumor growth both in vitro and in immunodeficient mice. To elucidate the mechanistic role of CXCR3, we conducted transcriptomic profiling of tumor xenografts, revealing that CXCR3 depletion would disrupt mitochondrial homeostasis. This was further supported by our findings that CXCR3 would localize to the mitochondrial membrane, and that inhibition of CXCR3 would lead to mitochondrial depolarization and increased reactive oxygen species production. Notably, activation of phosphorylated-STAT3 rescued cell viability in CXCR3-depleted cells, suggesting that CXCR3 may modulate mitochondrial function through a STAT3-dependent mechanism, consistent with the known functional role of STAT3 in maintaining mitochondrial redox balance. Furthermore, treatment with the selective CXCR3 antagonist AMG487 reduced tumor growth and disrupted mitochondrial function in vitro, in vivo, and in patient-derived GBM stem cells. Our findings reveal CXCR3 as a previously unrecognized regulator of mitochondrial function in cancer cells, positioning the CXCR3-mitochondrial signaling axis as a promising therapeutic target for GBM. Chemokine receptors are well-established mediators of inflammatory responses, emerging evidence suggests that these receptors may play roles beyond the immune system. In this study, we have demonstrated that CXCR3 would localize to the mitochondrial membrane and exert a previously unrecognized function in regulating cancer metabolism and mitochondrial function. Figure created using BioRender ( https://biorender.com ).</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":"11 1","pages":"143"},"PeriodicalIF":6.1,"publicationDate":"2025-04-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11971461/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143787987","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":"Combined anti-PD-L1 and anti-VEGFR2 therapy promotes the antitumor immune response in GBM by reprogramming tumor microenvironment.","authors":"Lin Yao, Hao Wang, Yongsheng Liu, Ming Feng, Yanyan Li, Zuopeng Su, Wen Li, Yun Xiong, Heyang Gao, Youxin Zhou","doi":"10.1038/s41420-025-02427-7","DOIUrl":"10.1038/s41420-025-02427-7","url":null,"abstract":"<p><p>Inhibitors of programmed cell death ligand 1 (PD-L1) and vascular endothelial growth factor receptor 2 (VEGFR2) are commonly used in the clinic, but they are beneficial for only a minority of glioblastoma multiforme (GBM) patients. GBM has significant immunosuppressive properties, and there are many immunosuppressive cells and dysfunctional effector T cells in the tumor microenvironment (TME), which is one of the important reasons for the failure of clinical treatment of GBM. Here, we have identified P21 activated kinase 4 (PAK4) as a pivotal immune suppressor in the TME. PAK4 is a threonine protein kinase, and PAK4 knockdown attenuates vascular abnormalities and promotes T-cell infiltration. In this study, our results showed that the expression of PAK4 was significantly downregulated after VEGFR2 knockdown. Next, we constructed a coculture system of CD8+ T cells and GBM cells. Our findings showed that combined anti-PD-L1 and anti-VEGFR2 therapy can regulate the TME and inhibit GBM cells' immune escape; overexpression of PAK4 can reverse this effect. Finally, we tested the combination therapy in mouse intracranial graft tumor models and found that combination therapy can prolong mouse survival. These findings suggest that anti-VEGFR2 therapy can downregulate PAK4, reprogram the TME by increasing cytotoxic CD8+ T cells infiltration and activation, and enhance the therapeutic effect of anti-PD-L1 therapy on GBM cells.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":"11 1","pages":"136"},"PeriodicalIF":6.1,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11968841/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143779010","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":"Ursodeoxycholic acid prompts glycolytic dominance, reductive stress and epithelial-to-mesenchymal transition in ovarian cancer cells through NRF2 activation.","authors":"Adrienn Sipos, Éva Kerekes, Dóra Szeőcs, Fanni Szarvas, Szandra Schwarcz, Emese Tóth, Gyula Ujlaki, Edit Mikó, Peter Bai","doi":"10.1038/s41420-025-02398-9","DOIUrl":"10.1038/s41420-025-02398-9","url":null,"abstract":"<p><p>Numerous secreted bacterial metabolites were identified with bioactivity in various neoplasias, including ovarian cancer. One such metabolite is ursodeoxycholic acid (UDCA), a secondary bile acid that has widespread beneficial effects in neoplasias. Hereby, we assessed the bioactivity of UDCA in cell models of ovarian cancer, by applying UDCA in concentrations corresponding to the serum reference concentrations of UDCA (300 nM). UDCA induced epithelial-to-mesenchymal transition (EMT), increased the flux of glycolysis and reduced the naturally occurring oxidative stress in ovarian cancer cells. These changes were dependent on the activation of NRF2. The tumoral overexpression of UDCA-induced genes in humans correlated with worse survival. These results point out that bacterial metabolites may have opposite effects in different neoplasias and raise the possibility that UDCA-containing remedies on the long run may support cancer progression in ovarian cancer patients.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":"11 1","pages":"134"},"PeriodicalIF":6.1,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11965337/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143771435","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}