Cell Death Discovery最新文献

{"title":"Saikosaponin‑D triggers cancer cell death by targeting the PIM1/c-Myc axis to reprogram oncogenic alternative splicing.","authors":"Xin Zhang, Xuehui Li, Feng Zhang, Dejun Yang, Qiang Sun, Yuang Wei, Ronglin Yan, Dongliang Xu, Shan Lin, Fuwen Yuan, Weijun Wang","doi":"10.1038/s41420-025-02729-w","DOIUrl":"10.1038/s41420-025-02729-w","url":null,"abstract":"<p><p>Saikosaponins (SSs, including SSA, SSB, SSC, and SSD), the major bioactive compounds in the traditional medicine Radix Bupleuri, are emerging agents exhibiting anti-tumor efficacy in several cancers. However, the respective anti-tumor efficacy of these agents and mechanisms in cancers remains unclear. Here, we reported that SSD, among SSs, possessed a significant anti-tumor role across different cancer types in vivo and in vitro by downregulating alternative splicing factors and rewiring oncogenic alternative splicing events. Mechanistically, SSD directly targets PIM1 and blocks the interaction between PIM1 and Myc, and decreases PIM1-mediated Myc phosphorylation at serine 62 and Myc protein stability, resulting in global restraining of Myc-governed alternative splicing factors transcription and inducing oncogenic alternative splicing rewiring. Transcript-specific ablation of SSD-regulated alternative spliced products with CIRSPR-Cas13 or targeting PIM1/Myc with specific small inhibitors significantly desensitizes cancer cells and patient-derived organoids (PDOs) to SSD treatments. These studies demonstrated the potent anti-tumor efficacy of SSD and exposed a PIM1/Myc axis by which SSD modulates the expression of an oncogenic alternative splicing regulatory network that mediates SSD's anti-tumor role in cancers.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":"11 1","pages":"427"},"PeriodicalIF":7.0,"publicationDate":"2025-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12501015/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145238211","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":"Rho-kinase inhibition reduces subretinal fibrosis.","authors":"Yuebing Li, Tural Yarahmadov, Laura Jahnke, Tess Brodie, Sophia C Morandi, Deborah Stroka, Ali Hafezi-Moghadam, Martin S Zinkernagel, Volker Enzmann, Souska Zandi","doi":"10.1038/s41420-025-02709-0","DOIUrl":"10.1038/s41420-025-02709-0","url":null,"abstract":"<p><p>Subretinal fibrosis, a consequence of choroidal neovascularization (CNV) in age-related macular degeneration (AMD), leads to irreversible vision loss due to excessive accumulation of extracellular matrix (ECM) proteins and fibrotic scarring. Anti-VEGF therapy can reverse neovascularization, but its effect on fibrosis is relatively limited. To reduce the visual impact of the fibrosis that remains after CNV. Our study investigated the use of ROCK inhibitors, fasudil and belumosudil, to treat subretinal fibrosis after CNV. The results confirmed that levels of key fibrotic markers (TGF-β1, fibronectin, vimentin, α-SMA and pMYPT1) were lower after treatment. IMC provided detailed spatial mapping of protein expression, revealing significant changes in structure and cellular composition before and after the treatment. We found that fasudil and belumosudil are effective in attenuating subretinal fibrosis by modulating the ROCK-signaling pathway, reducing ECM remodeling and attenuating the expression of markers associated with fibrosis. We hope to provide a basis for maximizing clinical benefit, focusing on optimizing dose and timing of treatment, exploring combination therapies for future anti-subretinal fibrosis research.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":"11 1","pages":"428"},"PeriodicalIF":7.0,"publicationDate":"2025-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12501381/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145238217","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":"Exploiting dysregulated iron homeostasis to eradicate persistent high-grade serous ovarian cancer.","authors":"Carmelo Cerra, Madeleine R C Tancock, Niko Thio, Ada Koo, AnnRann Wong, Karla J Cowley, Swati Varshney, Madelynne O Willis, Kaylene J Simpson, David D L Bowtell, Elaine Sanij, Elizabeth L Christie, Richard B Pearson, Jian Kang, Keefe T Chan","doi":"10.1038/s41420-025-02716-1","DOIUrl":"10.1038/s41420-025-02716-1","url":null,"abstract":"<p><p>Treatments for high-grade serous ovarian cancer (HGSOC) are initially effective but most invariably fail. Although they can successfully suppress the bulk of the tumour cell population, residual cancer cells can enter alternative therapy-resistant cell fates highlighted by proliferative arrest. Understanding the nature of these fates and how cells may resume uncontrolled proliferation will lead to the development of new treatments for HGSOC. In this study, we examine the response of HGSOC cells to standard of care cisplatin chemotherapy and to the RNA Polymerase I transcription inhibitor CX-5461/Pidnarulex, two drugs that elicit a potent DNA damage response and growth arrest. Here, we identify that HGSOC cells exposed to these therapies show multiple hallmarks of therapy-induced senescence (TIS) and derive a core TIS gene expression signature irrespective of genetic background or senescence trigger. Given that TIS is a potentially escapable state, we have performed a focussed drug screen to identify drugs that eradicate senescent HGSOC cells. We identify that therapy-induced senescent HGSOC cells, including those with decreased sensitivity to senolytic drugs that inhibit the pro-survival protein BCL-XL, can be eliminated using drugs that induce ferroptosis, an iron-dependent form of cell death. Mechanistically, we demonstrate that senescent HGSOC cells have altered expression of regulators of iron metabolism leading to intracellular iron overload that underpins this targetable vulnerability. Together, we highlight elevated levels of iron as a TIS biomarker in HGSOC and the potential of inducing ferroptosis to eradicate residual HGSOC cells following initial therapy.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":"11 1","pages":"423"},"PeriodicalIF":7.0,"publicationDate":"2025-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12462457/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145147871","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":"TRIM21 promotes colorectal cancer development through regulating DNA replication by TCF3/MCM2/5 axis.","authors":"Xintian Zhang, Han Yao, Yichao Hou, Kun Zhou, Yu Liang, Lidan Hou, Xingming Zhang, Wenfeng Wang, Leilei Du, Mengfei Yao, Jianhua Wang, Xiangjun Meng","doi":"10.1038/s41420-025-02722-3","DOIUrl":"10.1038/s41420-025-02722-3","url":null,"abstract":"<p><p>Disrupting DNA replication has been employed for treating cancers. In the present study, we found that Tripartite motif containing 21 (TRIM21) was highly expressed in colorectal cancer (CRC) and could be valuable for predicting the prognosis of CRC patients. Further study demonstrated that TRIM21 positively regulated the expression of MCM2 and MCM5, DNA replication and proliferation of CRC cells both in vitro and in vivo. In addition, TRIM21 knockdown inhibited both replication initiation and velocity, and increased the chemosensitivity of CRC cells to 5-FU and SN-38. Our study also revealed that DNA replication inhibition following TRIM21 knockdown could not be restored by cell cycle checkpoint kinase inhibitors, but partially by Transcription Factor 3 (TCF3) knockdown. TCF3 directly suppressed MCM2 and MCM5 transcription, inhibiting DNA replication. In summary, TRIM21 could influence tumor development and chemosensitivity to replication inhibitors by regulating DNA replication through the TCF3/MCM2/5 axis, suggesting a promising potential for CRC in the clinic.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":"11 1","pages":"422"},"PeriodicalIF":7.0,"publicationDate":"2025-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12462522/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145147962","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 long noncoding RNA-based serum signature predicts ado-trastuzumab emtansine (T-DM1) treatment benefit in HER2+ metastatic breast cancer patients: a multicenter cohort study.","authors":"Syed S Islam, Taher Al-Tweigeri, Asma Tulbah, Saleh N Najjar, Sarah S Aljohani, Layla Al-Harbi, Ahmed M Gad, Shafat Ujjahan, Abdelilah Aboussekhra","doi":"10.1038/s41420-025-02701-8","DOIUrl":"10.1038/s41420-025-02701-8","url":null,"abstract":"<p><p>Ado-trastuzumab is considered a standard treatment for patients with HER2+ metastatic breast cancer (mBC). Current clinical practices do not reliably predict therapeutic outcomes for patients who are refractory to therapy. Long noncoding RNAs (lncRNAs) are emerging as critical regulators of gene expression and therapeutic resistance, and the use of lncRNAs as tumor biomarkers is becoming more common in other diseases. However, whether they may also be used to predict therapy response in HER2+ mBC is unclear. Using lncRNA microarray profiling, we identified 23 differentially expressed lncRNAs in the serum of HER2+ mBC patients with unique responses to trastuzumab-emtansine (T-DM1). Following RT-PCR validation and machine learning-based selection in the training cohort, four lncRNAs were selected to construct the signature panel and used for T-DM1 response prediction. This four-lncRNA signature classifies patients into high- and low-risk groups and significantly and distinctively predicts patient survival. Importantly, identical outcomes were obtained from the two validation cohorts, confirming that the signature accurately predicts the T-DM1 response of HER2+ mBC patients. Integrative analysis demonstrated that this four-lncRNA signature is primarily released by immune and tumor cells and is correlated with immune activity. Our findings indicate that the four-lncRNA signature is a potentially promising biomarker for predicting T-DM1 treatment outcome, as it may reliably predict the T-DM1 treatment response in HER2+ mBC.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":"11 1","pages":"421"},"PeriodicalIF":7.0,"publicationDate":"2025-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12420834/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145029073","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":"Mesenchymal stem cells for lung diseases: focus on immunomodulatory action.","authors":"Yuqian Feng, Jiamin Lu, Jing Jiang, Kezhan Shen, Kaibo Guo, Yazhen Zhong, Shengyou Lin","doi":"10.1038/s41420-025-02303-4","DOIUrl":"10.1038/s41420-025-02303-4","url":null,"abstract":"<p><p>In recent years, the morbidity and mortality caused by acute and chronic lung diseases have gradually increased, becoming a global public health burden. However, modern medicine has yet to determine the exact treatment for lung diseases associated with inflammation. Alleviating lung diseases and repairing injured lung tissue are urgent issues that need to be resolved. Mesenchymal stem cells (MSCs) have been used to treat various inflammatory diseases owing to their powerful anti-inflammatory, anti-apoptotic, and tissue-regenerative properties. MSCs show great promise and have been shown to play a role in relieving lung diseases experimentally. The immune regulatory role of MSCs is thought to be a key mechanism underlying their multiple potential therapeutic effects. Immune cells and secreted factors contribute to tissue repair following lung injury. However, the overactivation of immune cells can aggravate lung injury. Here, we review evidence that MSCs act on immune cells to relieve lung diseases. Based on the immunomodulatory properties of MSCs, the specific mechanisms by which MSCs in alleviate lung diseases are reviewed, with a focus on innate and adaptive immunity. In addition, we discuss current challenges in the treatment of lung diseases using MSCs.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":"11 1","pages":"52"},"PeriodicalIF":7.0,"publicationDate":"2025-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12411635/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144999701","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":"Protein lipoylation in cancer: metabolic reprogramming and therapeutic potential.","authors":"Sainan Li, Yingchao Liu, Wanye Hu, Aoli Deng, Xueying Ren, Lulu Chen, Yajuan Lu, Yunyi Wu, Hangqi Huang, Jinghao Cao, Jing Du, Jun Xia, Yanchun Li","doi":"10.1038/s41420-025-02718-z","DOIUrl":"10.1038/s41420-025-02718-z","url":null,"abstract":"<p><p>Protein lipoylation, a mitochondria-specific post-translational modification (PTM) evolutionarily conserved from bacteria to mammals, plays critical role in metabolic processes. In humans, four identified lipoylated proteins serve as essential components of key enzymes involved in glycolysis, the tricarboxylic acid (TCA) cycle, and amino acid metabolism. The dynamic addition or removal of lipoylation modifications critically regulates the functional activity of these enzymes, with dysregulation strongly associated with cancers. Notably, cancer-associated metabolic reprogramming frequently coincides with functional impairment of lipoylated proteins, which subsequently modulates tumor growth through metabolic adaptation. In this review, we systematically summarized the biosynthesis of lipoic acid (LA), introduced the basic structure of lipoylated protein and presented the regulation of lipoylation. Since metabolic reprogramming is an important feature of tumorigenesis, we discussed the relationship between protein lipoylation and tumor metabolic reprogramming. Cuproptosis is a novel form of cell death characterized by copper-mediated lipoylation, which disrupts mitochondrial metabolism and induces cell death through the aggregation of lipoylated proteins in the TCA cycle. We highlighted the therapeutic potential of targeting lipoylation to disrupt cancer cell energy metabolism, particularly through cuproptosis. These insights reveal the intricate interplay between lipoylation and cancer progression and open new avenues for developing targeted therapies. Furthermore, we proposed innovative combinatorial strategies leveraging the crosstalk between cuproptosis and ferroptosis to overcome tumor drug resistance. These insights establish lipoylation as a promising therapeutic axis for developing precision cancer therapies targeting metabolic vulnerabilities.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":"11 1","pages":"420"},"PeriodicalIF":7.0,"publicationDate":"2025-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12405494/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144944537","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":"Overexpression miR-125a-5p inhibits HSCs activation and alleviates liver fibrosis through TGF-β/Smad2/3 signaling pathway and autophagy.","authors":"Chunyan Zhang, Yabin Zhao, Haoyu Yan, Jianlin Guo, GuoYing Yu","doi":"10.1038/s41420-025-02694-4","DOIUrl":"10.1038/s41420-025-02694-4","url":null,"abstract":"<p><p>Liver fibrosis represents an important pathological stage during chronic hepatopathy development, posing a significant threat to human health. Hepatic stellate cells (HSCs), an essential hepatic non-parenchymal cells, have a key effect on fibrogenesis, with their activation being a hallmark of liver fibrosis. MicroRNAs (miRNAs), the small non-coding RNAs, become the critical biomarkers and regulatory molecules in fibrotic processes. Among them, miR-125a-5p is implicated in cancer and inflammatory pathways, yet its functional role and mechanistic involvement in HSC activation remain poorly understood. According to our findings, miR-125a-5p expression was significantly decreased in TGF-β-activated HSC-T6 cells. Notably, ectopic miR-125a-5p overexpression effectively inhibited TGF-β-mediated HSC-T6 activation. Further mechanistic investigations revealed that miR-125a-5p attenuated HSC activation while ameliorating liver fibrosis through regulating the TGF-β/Smad2/3 pathway and autophagy. Additionally, TGFβR1 was miR-125a-5p's target gene. Collectively, miR-125a-5p negatively regulates HSC activation in liver fibrosis, exerting its anti-fibrotic activities through suppressing the TGF-β/Smad2/3 pathway and autophagy modulation.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":"11 1","pages":"419"},"PeriodicalIF":7.0,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12402229/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144944576","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":"SPANXB1 drives brain metastasis in breast cancer via MMP1 regulation: potential therapeutic insights with metformin.","authors":"Qi Wang, Haofeng Wu, Zhaoyi Zhai, Dongliang Fang, Chun Yang, Li Liu, Xiaowei Jia, Baopu Du, Yingqi Lyu, Mingshan Zhang, Tao Lu, Lulu Wang, Yan Gao","doi":"10.1038/s41420-025-02721-4","DOIUrl":"10.1038/s41420-025-02721-4","url":null,"abstract":"<p><p>Cancer-testicular antigens (CTAs) have been considered as potential prognostic biomarkers and therapeutic targets due to their specific expression and roles in tumorigenesis and metastasis. Among these, the function and mechanism of SPANXB1 in breast cancer brain metastasis (BCBM) remain poorly understood. In this study, we investigated the role of SPANXB1 in BCBM. Our results demonstrated that SPANXB1 was highly expressed in brain-tropic breast cancer cells and brain metastasis samples. Functional assays revealed that SPANXB1 promoted breast cancer cell invasion, migration, vasculogenic mimicry (VM) formation, and blood-brain barrier (BBB) extravasation, thereby accelerating the process of brain metastasis. Mechanistically, SPANXB1 facilitated chromatin opening at the MMP1 promoter region via histone H3R17me2 modification and upregulated transcription factor YY1, leading to increased MMP1 expression. In vivo experiments further confirmed the role of SPANXB1 in enhancing brain metastasis. Notably, metformin effectively inhibited the expression of SPANXB1 and MMP1, thereby attenuating BCBM progression. The present study indicates the potential of SPANXB1 as a diagnostic and therapeutic target for BCBM. Additionally, our findings suggest metformin as a promising therapeutic strategy for this highly aggressive disease.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":"11 1","pages":"418"},"PeriodicalIF":7.0,"publicationDate":"2025-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12398519/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144944672","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":"Reduction of lymphotoxin beta receptor induces cellular senescence via the MDMX-p53 pathway.","authors":"So Young Kim, Bin Lee, Je-Jung Lee, Man Sup Kwak, Woo Joong Rhee, In Ho Park, Jeon-Soo Shin","doi":"10.1038/s41420-025-02708-1","DOIUrl":"10.1038/s41420-025-02708-1","url":null,"abstract":"<p><p>The lymphotoxin β receptor (LTβR), a key activator of non-canonical NF-κB signaling, is expressed in various cells, including cancer cells. Although high expression of LTβR has been associated with poor patient prognosis and drug resistance, conflicting evidence suggested that LTβR induces apoptosis. To investigate the functional role of LTβR in tumors, we performed LTβR knockdown in cancer cells. We found that LTβR knockdown induced senescence phenomena such as reduced cell number; increased cell size; increased SA-β-Gal activity; and upregulated p53, MDM2 and p21 expression. Moreover, LTβR knockdown induced p21-mediated senescence in p53 WT cancer cells, but not in p53 mutant cancer cells. The level of p53 is regulated by MDM2 and MDMX; MDMX enhances MDM2 activity but is also subject to MDM2-mediated degradation in the nucleus. We found that the intracellular domain of LTβR bound to MDMX thereby inhibited its nuclear translocation, which in turn reduced MDMX ubiquitination and consequently promoted p53 ubiquitination. Additionally, tumors derived from B16F10^LTβR-KO cells in WT mice exhibited significantly reduced growth compared to those derived from B16F10^WT cells. These results demonstrate that LTβR regulates p53 protein levels by modulating MDMX stability and localization, resulting in p53-mediated cellular senescence. LTβR regulates p53-mediated senescence by inhibiting MDMX nuclear translocation and degradation. LTβR interacts with MDMX in the cytoplasm, preventing its nuclear translocation and degradation under normal conditions (dotted arrows). When LTβR is depleted, MDMX is translocated into the nucleus by MDM2, and undergoes degradation (solid arrows). This reduces p53 degradation and consequently activates p53, leading to p21 transcription and the induction of cellular senescence. Treatment with doxorubicin (Dox) or nutlin-3a further enhances p53-mediated transcriptional activation of p21, and their combination with LTβR depletion exerts an additive effect in promoting cellular senescence.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":"11 1","pages":"416"},"PeriodicalIF":7.0,"publicationDate":"2025-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12397326/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144944559","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}