Cell Death & Disease最新文献

{"title":"TUFT1 regulates cancer progression by suppressing centrosome amplification and mitotic spindle multipolarity.","authors":"Shaojie Feng, Mengmeng Zhao, Donghui Zhang, Yan Zhang, Lingyuan Min, Xianqiang Liu, Huan Shi, Tianning Wang","doi":"10.1038/s41419-025-08010-3","DOIUrl":"10.1038/s41419-025-08010-3","url":null,"abstract":"<p><p>Centrosome amplification (CA) has been observed in various solid tumors and contributes to chromosomal instability (CIN) and poor clinical prognosis in patients with cancer. CA also inhibits cell proliferation by inducing cell-cycle arrest and cell death. However, the mechanism of regulation of centrosome number in cancer cells and its effect on CIN and cell proliferation remains elusive. Here, we report that tuftelin (TUFT1) is a novel centrosomal protein that localizes to the proximal ends of parent centrioles. TUFT1 prevents CA and mitotic spindle multipolarity by suppressing premature polo-like kinase 1 activation. In addition, TUFT1 is phosphorylated by NIMA-related kinase 2 (NEK2), and the phosphorylation status of TUFT1 is essential for coordinating centrosome number and cell proliferation in cervical and breast cancers. Data from clinical breast cancer samples indicate that the combined detection of TUFT1 and NEK2 expression reflects tumor malignancy and patient survival with higher precision. Overall, these results reveal a crucial role of TUFT1 in the regulation of tumor progression through centrosome number control. Thus, TUFT1 represents a promising target for diagnostic and therapeutic approaches for cancers.</p>","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"16 1","pages":"673"},"PeriodicalIF":9.6,"publicationDate":"2025-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12480466/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145191350","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Retraction Note: Downregulation of the Rho GTPase pathway abrogates resistance to ionizing radiation in wild-type p53 glioblastoma by suppressing DNA repair mechanisms.","authors":"Yuli Thamires Magalhaes, Viktor Kalbermatter Boell, Giovanna Duo Cardella, Fabio Luis Forti","doi":"10.1038/s41419-025-08071-4","DOIUrl":"10.1038/s41419-025-08071-4","url":null,"abstract":"","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"16 1","pages":"671"},"PeriodicalIF":9.6,"publicationDate":"2025-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12457582/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145130082","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CircPSD3 aggravates tumor progression by maintaining TCA cycle and mitochondrial function via regulating SUCLG2 in thyroid carcinoma.","authors":"Yijia Sun, Beinan Han, Jiawei Ge, Zijun Huo, Jin Li, Bo Lin, Xin Du, Yimin Zhang, Haiyan Weng, Shuang Yu, Yanbing Li, Haipeng Xiao, Xiaorong Lin, Shubin Hong","doi":"10.1038/s41419-025-07856-x","DOIUrl":"10.1038/s41419-025-07856-x","url":null,"abstract":"<p><p>In recent years, there has been a rapid increase in the incidence of thyroid carcinoma (TC). Our study focuses on the regulatory effect of circular RNAs on metabolism of TC, aiming to provide new insights into the mechanisms of progression and a potential therapeutic target for TC. In this study, we identified high expression levels of circPSD3 in TC tissues through RNA sequencing. Papillary thyroid cancer tissue cohorts verified the circPSD3 expression level was positively correlated with larger tumor size. circPSD3 promoted the proliferation of TC cells and reduced apoptosis both in vitro and in vivo. Proteomics and metabolomics suggested that circPSD3 might play a crucial role in regulating the tricarboxylic acid (TCA) cycle. Specifically, circPSD3 acted as a miR-338-5p sponge to upregulate SUCLG2, an enzyme of the TCA cycle, which accelerates the conversion of α-ketoglutarate (α-KG) to succinate. Knockdown of circPSD3 disrupts the TCA cycle and impairs mitochondrial function, resulting in decreased membrane potential and aerobic respiration rate. The reduction in mitochondrial function resulted in the inhibition of proliferation and initiation of mitochondria-mediated apoptosis.</p>","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"16 1","pages":"590"},"PeriodicalIF":9.6,"publicationDate":"2025-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12420806/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145029097","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction: Serglycin induces osteoclastogenesis and promotes tumor growth in giant cell tumor of bone.","authors":"Yunfei He, Dongdong Cheng, Cheng Lian, Yingjie Liu, Wenqian Luo, Yuan Wang, Chengxin Ma, Qiuyao Wu, Pu Tian, Dasa He, Zhenchang Jia, Xianzhe Lv, Xue Zhang, Zhen Pan, Jinxi Lu, Yansen Xiao, Peiyuan Zhang, Yajun Liang, Qingcheng Yang, Guohong Hu","doi":"10.1038/s41419-025-07629-6","DOIUrl":"10.1038/s41419-025-07629-6","url":null,"abstract":"","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"16 1","pages":"670"},"PeriodicalIF":9.6,"publicationDate":"2025-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12413457/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145005927","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Tissue-specific iron levels modulate lipid peroxidation and the FLASH radiotherapy effect.","authors":"Nuria Vilaplana-Lopera, Jiyoung Kim, Gilyeong Nam, Iain D C Tullis, Salome Paillas, Jia-Ling Ruan, Pei Ju Lee, Yanyan Jiang, Sohee Park, Tianxu Hou, Ayesha Nasir, Eve Charlesworth, Ellie Walker, Ammar Abu-Halawa, Mark A Hill, Changhoon Choi, Ik Jae Lee, Youngtae Jeong, Samira Lakhal-Littleton, Chee Kin Then, Shing-Chuan Shen, Amato J Giaccia, Kristoffer Petersson, Eui Jung Moon","doi":"10.1038/s41419-025-07988-0","DOIUrl":"10.1038/s41419-025-07988-0","url":null,"abstract":"<p><p>Iron is vital to living cells, playing a key role in cellular respiration, DNA synthesis, and various metabolic functions. Importantly, cancer cells have a higher dependency on iron compared to normal cells to support their rapid growth and survival. Due to this fact, tumors are more vulnerable to ferroptosis, an iron-dependent form of regulated cell death. Radiation therapy (RT), a standard treatment for many cancer patients, is known to induce ferroptosis. Ultra-high dose rate FLASH RT offers an improved therapeutic window by minimizing damage to normal tissues while preserving tumor control. However, the precise biological mechanisms behind the protective effects of FLASH RT on normal tissues remain unclear. In this study, we propose that variations in lipid peroxidation and ferroptosis, driven by intrinsic differences in iron levels between normal and cancerous tissues, contribute to this effect. Our findings show that FLASH RT increases lipid peroxidation and induces ferroptosis in tumor cells but does not significantly elevate lipid peroxidation and ferroptosis in normal tissues compared to conventional RT. To determine whether raising iron levels in normal tissues could abrogate the protective effects of FLASH, mice were fed a high-iron diet before RT. A high-iron diet before and after RT reversed the protective effect of FLASH, resulting in increased intestinal damage and lipid peroxidation. This suggests that baseline iron levels and iron-driven lipid peroxidation are critical factors in mediating the protective outcomes of FLASH RT. Overall, our study sheds light on the role of iron in modulating RT responses and provides new mechanistic insights into how FLASH RT influences normal and cancerous tissues.</p>","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"16 1","pages":"668"},"PeriodicalIF":9.6,"publicationDate":"2025-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12405469/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144944355","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeted deprivation of STAT6 sensitizes acute lymphoblastic leukemia cells to cytarabine in vivo and in vitro: clinical implications.","authors":"Shuzhang Sun, Yixuan Cheng, Xiange Huang, Yinjie Yan, Wanxin Hou, Houshun Fang, Yao Chen, Chunshuang Ma, Yiming Lu, Zhiyi Zhou, Yehuda G Assaraf, Hui Li, Hegen Li, Ning Xiao","doi":"10.1038/s41419-025-07981-7","DOIUrl":"10.1038/s41419-025-07981-7","url":null,"abstract":"<p><p>Chemotherapy is the leading treatment for acute lymphoblastic leukemia (ALL). However, many ALL patients eventually develop relapses, the treatment of which remains a major challenge due to their chemoresistance phenotype. As a step towards this end, we here uncovered that relapsed ALL specimens exhibit a significantly lower expression of STAT6 but not of other STATs, when compared with their paired diagnosis specimens. Furthermore, STAT6 plays a distinctive role in chemosensitization of ALL cells to cytarabine (Ara-C), and T-box transcription factor 21 (TBX21) emerged as a plausible intrinsic biomarker of this Ara-C chemosensitization. We demonstrate that STAT6 undergoes SUMOylation on Lys-307 and sentrin/SUMO-specific protease 3 (SENP3)-mediated deSUMOylation in ALL cells. Most importantly, Ara-C specifically induced SENP3 expression and SENP3 knockdown sensitized ALL cells to Ara-C, with an impact equivalent to STAT6 knockout. These findings support the feedback resistance conferred upon ALL cells by Ara-C-induced SENP3 expression. Our findings uncover a novel role for STAT6 in ALL resistance to Ara-C and suggest that its targeted deprivation or pharmacological inhibition specifically sensitizes ALL cells to Ara-C, offering a plausible modality to surmount Ara-C resistance in future ALL treatment.</p>","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"16 1","pages":"669"},"PeriodicalIF":9.6,"publicationDate":"2025-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12405434/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144944214","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Hepatocellular carcinoma stem cells: the current state of small molecule-based inhibitors.","authors":"Sara P Neves, Larissa M Bomfim, Daniel P Bezerra","doi":"10.1038/s41419-025-07983-5","DOIUrl":"10.1038/s41419-025-07983-5","url":null,"abstract":"<p><p>Hepatocellular carcinoma (HCC) is the most common type of liver cancer, accounting for over 90% of all cases. Patients with advanced-stage HCC are referred to systemic treatment. Although some advances in HCC therapy have been made in recent years, the prognosis for patients remains poor due to drug resistance, tumor relapse, and metastasis, implying that overall survival remains a challenge. Many studies have shown that tumor-initiating stem cells, also known as cancer stem cells (CSCs), play essential roles in tumorigenesis, metastasis, and treatment resistance in HCC and that future cancer treatments could be significantly improved by targeting this cell population subset. Different markers of CSCs from HCC have been identified, and intracellular signaling pathways and extracellular factors have been reported as targets capable of removing this cell subpopulation, highlighting the possibility of developing targeted drugs to eradicate HCC CSCs. In this review, we highlight emerging small compounds that target HCC CSCs to provide new insights and guide future research. Drugs in the preclinical and clinical trial development stages were selected and discussed.</p>","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"16 1","pages":"666"},"PeriodicalIF":9.6,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12402491/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144944312","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"TIGIT in cancer: from mechanism of action to promising immunotherapeutic strategies.","authors":"Haozhe Cui, Mawieh Hamad, Eyad Elkord","doi":"10.1038/s41419-025-07984-4","DOIUrl":"10.1038/s41419-025-07984-4","url":null,"abstract":"<p><p>TIGIT immune checkpoint (IC) has attracted great interest in recent years. It belongs to the PVR-like protein family, and it inhibits T and NK cell cytotoxic activities. TIGIT mediates its inhibitory effect by direct signaling through the cytoplasmic tail, CD155-mediated inhibition, or competition with the immune-activating receptor CD226. Preclinical observations from studies involving TIGIT-specific blocking monoclonal antibodies (mAbs) are promising, but the results of the clinical trials using anti-TIGIT mAb monotherapy were not favorable, which prompted a focus on combinational therapies. Some alternative approaches have the potential to avoid limitations, including low penetration, immunogenicity and safety of mAbs. This review addresses the mechanisms underlying TIGIT-mediated immune suppression. Additionally, promising immunotherapeutic approaches against TIGIT, including co-inhibition of TIGIT with other ICs, using small molecule inhibitors, blocking the TIGIT/PVR pathway using CAR-T cells and the current state of clinical trials as well as future directions, are discussed.</p>","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"16 1","pages":"664"},"PeriodicalIF":9.6,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12402281/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144944336","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Supercharged NK cells: a unique population of NK cells capable of differentiating stem cells and lysis of MHC class I high differentiated tumors.","authors":"Kawaljit Kaur, Po-Chun Chen, Anahid Jewett","doi":"10.1038/s41419-025-07986-2","DOIUrl":"10.1038/s41419-025-07986-2","url":null,"abstract":"<p><p>This study highlights the significance of supercharged NK (sNK) cells in inducing the lysis and differentiation of tumors at much higher levels compared to primary activated NK cells. sNK cells-induced higher release of growth factors, cytokines, and chemokines when compared to primary activated NK cells. When we used a similar level of IFN-γ from primary activated NK cells and sNK cells, the IFN-γ secreted from sNK cells exhibited greater potential to induce differentiation in both oral and pancreatic tumors. It is long known in the field of NK cells that primary NK cells induce significant lysis of stem-like/poorly differentiated tumors, but differentiated tumors are generally resistant to primary NK cell-mediated lysis. sNK cells, unlike primary activated NK cells, are found to highly target stem-like as well as differentiated tumors, indicating sNK cells can target not only tumors specific to NK cells but also those targeted by CD8+ T cells. Differentiation by sNK cells was inhibited less by the antibodies to IFN-γ and TNF-α when compared to that mediated by the primary activated NK cells, suggesting the role of other unexplored mechanisms in sNK cell-induced tumor differentiation. Overall, this study suggests the role of sNK cells in targeting the heterogeneous population of tumors, likely mediating the functions of both NK cells and T cells in controlling tumors, and inducing them to be effectively targeted by chemotherapy.</p>","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"16 1","pages":"665"},"PeriodicalIF":9.6,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12402122/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144944253","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"YY1-induced USP43 drives ferroptosis suppression by FASN stabilization and subsequent activation of SLC7A11 in ovarian cancer.","authors":"Tianyi Zhao, Xiaojun Chen, Jiangchun Wu, Siyu Chen, Yu Gan, Chaohua Liu, Xinyu Ha, Yangjun Wu, Xiang Zhou, Yong Wu, Xiaohua Wu","doi":"10.1038/s41419-025-07886-5","DOIUrl":"10.1038/s41419-025-07886-5","url":null,"abstract":"<p><p>The ubiquitin-specific protease (USP) family is a major member of the deubiquitinating enzyme family that plays important and diverse roles in multiple tumors. The roles and mechanisms of action of USP family members in ovarian cancer are not well understood. This study aimed to screen all the USP family members and explored the specific function of USP43 in ovarian cancer. The expression levels of USP family members in ovarian cancer were screened using bioinformatics analysis, and the specific function of USP43 was explored through in vitro and in vivo experiments. Functional assays, including cell viability, ferroptosis, and tumor xenograft models, were employed. In short, USP43 drives the ferroptosis suppression by activating the expression of SLC7A11 through FASN-HIF1α pathway. USP43 is an important prognostic factor for ovarian cancer, with its overexpression promoting ovarian cancer progression and its knockdown inhibiting it. Mechanistically, USP43, which is transcriptionally activated by YY1, stabilizes FASN through deubiquitination, and FASN activates SLC7A11 expression by stabilizing HIF1α. Furthermore, the combination of cisplatin and the SLC7A11 inhibitor HG106 significantly inhibits the growth of ovarian tumors. Thus, targeting the USP43-FASN-HIF1α-SLC7A11 axis can inhibit ferroptosis and promote platinum sensitivity in ovarian cancer.</p>","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"16 1","pages":"589"},"PeriodicalIF":9.6,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12402158/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144944452","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}