Cell Death Discovery最新文献_第2页

The role of cellular senescence in cardiovascular disease. 细胞衰老在心血管疾病中的作用。

IF 7 2区生物学

Cell Death Discovery Pub Date : 2025-10-06 DOI: 10.1038/s41420-025-02720-5

Chengying Xu, Zhimei Qiu, Qing Guo, Youyang Huang, Yongchao Zhao, Ranzun Zhao

{"title":"The role of cellular senescence in cardiovascular disease.","authors":"Chengying Xu, Zhimei Qiu, Qing Guo, Youyang Huang, Yongchao Zhao, Ranzun Zhao","doi":"10.1038/s41420-025-02720-5","DOIUrl":"10.1038/s41420-025-02720-5","url":null,"abstract":"The incidence of cardiovascular diseases rises significantly with age, making it one of the leading causes of death and disability worldwide, and cellular senescence plays a crucial role in this process. Cellular senescence constitutes a salient feature of organismal aging and stands as an independent risk factor for a range of cardiovascular diseases, encompassing hypertension, atherosclerosis, myocardial infarction, heart failure, and arrhythmia. This comprehensive review endeavors to comprehensively delineate the intricate regulatory mechanisms underlying cellular senescence and its attendant biological implications, while elucidating the profound implications of this process on the initiation and progression of cardiovascular diseases. Finally, we will delve into a spectrum of targeted interventions aimed at cellular senescence, specifically focusing on eliminating the accumulation of senescent cells during disease progression or inhibiting the inherent cellular senescence processes. Our ultimate goal is to mitigate or postpone the onset of diseases that are intricately linked to cellular senescence. A profound comprehension and rigorous investigation into the regulatory mechanisms of cellular senescence and their intricate interrelationships hold significant potential to furnish invaluable scientific evidence for the prevention and therapeutic strategies against cardiovascular diseases.","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":"11 1","pages":"431"},"PeriodicalIF":7.0,"publicationDate":"2025-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12501035/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145238146","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}

引用次数: 0

Plin4 modulates lipid droplet accumulation and ferroptosis in neurons exposed to benzo[a]pyrene. Plin4调节暴露于苯并[a]芘的神经元的脂滴积累和铁下垂。

IF 7 2区生物学

Cell Death Discovery Pub Date : 2025-10-06 DOI: 10.1038/s41420-025-02747-8

Hongyu Sun, Zhirui Ma, Xingdi Guo, Jie Chen, Hui He, Xiaomin Tong, Tingyu Ji, Shihan Ding, Chaoli Zhou, Yi Lyu, Fengjie Tian, Jinping Zheng

{"title":"Plin4 modulates lipid droplet accumulation and ferroptosis in neurons exposed to benzo[a]pyrene.","authors":"Hongyu Sun, Zhirui Ma, Xingdi Guo, Jie Chen, Hui He, Xiaomin Tong, Tingyu Ji, Shihan Ding, Chaoli Zhou, Yi Lyu, Fengjie Tian, Jinping Zheng","doi":"10.1038/s41420-025-02747-8","DOIUrl":"10.1038/s41420-025-02747-8","url":null,"abstract":"Benzo[a]pyrene (B[a]P), an environmental neurotoxin, induces cognitive decline through ferroptosis-mediated mechanisms. Transcriptomic analysis (GSE75206) of B[a]P-exposed mouse hippocampus identified 1668 differentially expressed genes, with Plin4 emerging as a key regulator linked to ferroptosis and lipid droplet (LD) accumulation. Behavioral tests confirmed hippocampal-dependent cognitive impairment and Plin4 upregulation. Molecular analyses demonstrated ferroptosis activation, evidenced by altered expression of related genes (Gpx4, Slc7a11, Ptgs2) and biochemical markers of lipid peroxidation and iron imbalance. In HT22 cells, Benzopyrene-7,8-Diol-9,10-Epoxide (BPDE) dose-dependently elevated Plin4 expression, inducing mitochondrial damage and ferroptosis. Silencing Plin4 reversed BPDE-induced ferroptosis by restoring redox balance, reducing LD accumulation, and improving mitochondrial integrity. Mechanistically, Plin4 amplifies B[a]P neurotoxicity by exacerbating iron overload and LD accumulation, sensitizing neurons to ferroptosis. This study identifies Plin4 as a central mediator of environmental pollutant-induced neurodegeneration and proposes it as a therapeutic target for ferroptosis-related cognitive disorders.","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":"11 1","pages":"442"},"PeriodicalIF":7.0,"publicationDate":"2025-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12500938/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145238151","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}

引用次数: 0

Hydrogen sulfide protects against spinal cord pyroptosis via persulfidation of Rac1 after lumbosacral plexus nerve injury. 腰骶丛神经损伤后，硫化氢可通过Rac1过硫化防止脊髓焦下垂。

IF 7 2区生物学

Cell Death Discovery Pub Date : 2025-10-06 DOI: 10.1038/s41420-025-02736-x

Jianyu Mao, Jiajia Lu, Sheng Wang, Xin Jiang, Jing Li, Qiang Fu, Nan Lu, Lei Zhu, Aimin Chen, Jun Ma

{"title":"Hydrogen sulfide protects against spinal cord pyroptosis via persulfidation of Rac1 after lumbosacral plexus nerve injury.","authors":"Jianyu Mao, Jiajia Lu, Sheng Wang, Xin Jiang, Jing Li, Qiang Fu, Nan Lu, Lei Zhu, Aimin Chen, Jun Ma","doi":"10.1038/s41420-025-02736-x","DOIUrl":"10.1038/s41420-025-02736-x","url":null,"abstract":"Pyroptosis, a form of lytic and inflammatory programmed cell death mediated by gasdermin proteins, contributes to progressive spinal cord neurodegeneration following neural trauma. Nevertheless, the regulatory mechanisms governing this process remain inadequately characterized. In this investigation, hydrogen sulfide (H₂S) was identified as an endogenous inhibitor of neuronal pyroptosis, functioning through Rac1-dependent NLRP3 inflammasome signaling. In a rat model of lumbosacral plexus nerve injury, H₂S treatment significantly decreased pyroptosis-associated markers (NLRP3, caspase-1, GSDMD) and enhanced neuronal survival. In vitro, the administration of H₂S effectively mitigated hypoxia-induced neuronal pyroptosis by inhibiting the assembly of the NLRP3 inflammasome. Mechanistically, our findings indicate that H₂S selectively persulfidates Rac1, inhibiting its GTPase activity and reducing reactive oxygen species (ROS) production, both of which are critical for inflammasome priming. Molecular dynamics simulations and site-directed mutagenesis further confirmed that H₂S persulfidation of Rac1 at Cys178 alters its conformation, thereby suppressing NLRP3 inflammasome activation. Taken together, our findings reveal a novel post-translational regulatory mechanism by which H₂S mitigates pyroptotic neuronal death through Rac1 persulfidation, highlighting the H₂S-Rac1 axis as a promising therapeutic target for neuroprotection in pyroptosis-related neurodegeneration.","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":"11 1","pages":"436"},"PeriodicalIF":7.0,"publicationDate":"2025-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12500895/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145238166","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}

引用次数: 0

A knock-in mouse model for GABRG2-related epileptic encephalopathy displays spontaneous generalized seizures and cognitive impairment. gabrg2相关癫痫性脑病小鼠敲入模型显示自发性全身性癫痫发作和认知障碍。

IF 7 2区生物学

Cell Death Discovery Pub Date : 2025-10-06 DOI: 10.1038/s41420-025-02759-4

Dingding Shen, Jiali Wan, Xin Zhang, Jiahui Sui, Longwu Zhan, Yuqin Zheng, Yaohui Ni, Qi Zhang

{"title":"A knock-in mouse model for GABRG2-related epileptic encephalopathy displays spontaneous generalized seizures and cognitive impairment.","authors":"Dingding Shen, Jiali Wan, Xin Zhang, Jiahui Sui, Longwu Zhan, Yuqin Zheng, Yaohui Ni, Qi Zhang","doi":"10.1038/s41420-025-02759-4","DOIUrl":"10.1038/s41420-025-02759-4","url":null,"abstract":"De novo mutations in voltage- and ligand-gated ion channels have been associated with an increasing number of cases of developmental and epileptic encephalopathies (DEEs), which often fail to respond to classic antiseizure medications. A de novo mutation (c.C316G > A, p.A106T) in the human GABA type-A receptor γ2 subunit gene (GABRG2) has been recurrently identified in patients with DEE. In this study, we generated a knock-in mouse model replicating the human GABRG2(A106T) variation (Gabrg2+/A105T in mouse). Gabrg2+/A105T mice displayed early mortality, spontaneous seizures, and heightened seizure susceptibility. Behavioral analysis revealed phenotypes consistent with DEE, including impaired spatial learning and memory, as well as increased anxiety-like behavior. Reduced γ2 subunit protein expression was detected in the hippocampus of mutant mice, but not other brain regions. Electrophysiological recordings revealed a significant decrease in the amplitude of miniature inhibitory postsynaptic currents (mIPSCs), indicating impaired synaptic GABAergic inhibition. Notably, hippocampal transcriptome profiling provided evidence of neuroinflammation, and histological analysis demonstrated neuronal loss and microglia activation prior to seizure onset. These findings indicate that neuroinflammatory processes, a major theme in acquired epilepsies, may potentially exacerbate epileptogenesis in Gabrg2+/A105T mice. The knock-in mouse model serves as a potential model for evaluating anti-inflammatory therapies as adjunct treatments for drug-resistant DEEs.","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":"11 1","pages":"443"},"PeriodicalIF":7.0,"publicationDate":"2025-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12501280/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145238060","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}

引用次数: 0

Modulation of stress granules by lobeline increases cell death in hypoxia and impacts the ability of glioblastoma cells to secrete extracellular vesicles. 血红素对应激颗粒的调节增加了缺氧条件下的细胞死亡，并影响了胶质母细胞瘤细胞分泌细胞外囊泡的能力。

IF 7 2区生物学

Cell Death Discovery Pub Date : 2025-10-06 DOI: 10.1038/s41420-025-02692-6

Kathleen M Attwood, Lauren P Westhaver, Aaron Robichaud, Jae Ho Han, Sydney Croul, Gabriel Wajnberg, Jeremy W Roy, Adrienne C Weeks

{"title":"Modulation of stress granules by lobeline increases cell death in hypoxia and impacts the ability of glioblastoma cells to secrete extracellular vesicles.","authors":"Kathleen M Attwood, Lauren P Westhaver, Aaron Robichaud, Jae Ho Han, Sydney Croul, Gabriel Wajnberg, Jeremy W Roy, Adrienne C Weeks","doi":"10.1038/s41420-025-02692-6","DOIUrl":"10.1038/s41420-025-02692-6","url":null,"abstract":"Glioblastoma (GBM) is a devastating universally fatal primary brain cancer. Novel therapeutic strategies are required to alter disease course and improve survival in these patients. There is increasing evidence that modulating cancer's ability to respond to and survive cellular stress through RNA stress granules (SGs) may be a novel approach to cancer therapeutics. SGs are cytoplasmic aggregates of untranslated mRNAs and RNA binding proteins formed in response to a variety of cellular stressors, that allow cells to temporarily prioritize translation of stress-related proteins. A previous drug screen identified the dopamine modulator lobeline as a factor affecting SG disassembly in GBM cells. Lobeline impairs GBM cell survival by impairing SG disassembly after hypoxia. Specifically, after a hypoxic challenge, lobeline \"locks\" cells in a stressed state, even after re-exposure to normoxia. This is characterized by retained SGs, elevated levels of phosphorylated eIF2α and a sustained reduction in global protein translation. The disruption of the canonical stress response induced by lobeline ultimately results in increased cell death in both primary and immortalized GBM cell lines. Interestingly, lobeline also reduces post-hypoxia extracellular vesicle (EV) release, potentially through sequestration of the SG and EV protein, YBX1. Taken together, this adds to the literature that modulating stress and SG dynamics may be useful alone or to potentiate other treatment modalities affecting stress in GBM.","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":"11 1","pages":"432"},"PeriodicalIF":7.0,"publicationDate":"2025-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12501001/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145238161","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}

引用次数: 0

Nelfinavir triggers ferroptosis by inducing ER stress mediated downregulation of GPX4/GSH system, upregulation of NRF2/HO-1 axis, and mitochondrial impairment in hepatocellular carcinoma cells. 奈非那韦通过诱导内质网应激介导的GPX4/GSH系统下调、NRF2/HO-1轴上调和肝癌细胞线粒体损伤触发铁凋亡。

IF 7 2区生物学

Cell Death Discovery Pub Date : 2025-10-06 DOI: 10.1038/s41420-025-02761-w

Lei Zhang, Xuejun Wang

{"title":"Nelfinavir triggers ferroptosis by inducing ER stress mediated downregulation of GPX4/GSH system, upregulation of NRF2/HO-1 axis, and mitochondrial impairment in hepatocellular carcinoma cells.","authors":"Lei Zhang, Xuejun Wang","doi":"10.1038/s41420-025-02761-w","DOIUrl":"10.1038/s41420-025-02761-w","url":null,"abstract":"Hepatocellular carcinoma (HCC) is one of the most common malignancies with poor prognosis. Novel therapeutic strategies for HCC are urgently needed. Ferroptosis, an iron and reactive oxygen species (ROS) dependent regulated cell death, emerges to efficiently abrogate the growth and proliferation of HCC cells. The identification of new ferroptosis inducing agents should provide potential therapeutics for more effective management of HCC. Here we have identified nelfinavir, a human immunodeficiency virus (HIV) protease inhibitor as a novel ferroptosis inducer in HCC cells, Hepa1-6 and HepG2. Mechanistically, the induction of ferroptosis by nelfinavir required its induction of ER stress; suppression of ER stress remarkably attenuated mitochondrial impairment and superoxide production, the autophagic degradation of GPX4, and increases in the labile iron pool associated with the activation of the nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) axis in nelfinavir-treated HCC cells. In a mouse model of HCC xenografts, nelfinavir treatment significantly suppressed tumor growth, and this effect was more pronounced when nelfinavir and sorafenib were administered together. Collectively, we demonstrate that nelfinavir can induce ferroptosis in an ER stress dependent manner, thereby identifying a new inducer of ferroptosis that can potentially be repurposed to treat HCC.","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":"11 1","pages":"444"},"PeriodicalIF":7.0,"publicationDate":"2025-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12501057/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145238129","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}

引用次数: 0

HUWE1 loss promotes stemness and drug resistance in CRC with dysregulated β-catenin destruction complex. HUWE1缺失促进结直肠癌中β-连环蛋白破坏复合物失调的茎秆和耐药。

IF 7 2区生物学

Cell Death Discovery Pub Date : 2025-10-06 DOI: 10.1038/s41420-025-02731-2

Chanhaeng Lee, Sang-Hee Park, Inn-Oc Han, Sungjoo Kim Yoon

{"title":"HUWE1 loss promotes stemness and drug resistance in CRC with dysregulated β-catenin destruction complex.","authors":"Chanhaeng Lee, Sang-Hee Park, Inn-Oc Han, Sungjoo Kim Yoon","doi":"10.1038/s41420-025-02731-2","DOIUrl":"10.1038/s41420-025-02731-2","url":null,"abstract":"Cancer stem cells (CSCs) are a key driver of tumor initiation, progression, and drug resistance in colorectal cancer (CRC). The Wnt/β-catenin signaling pathway, which is hyperactivated in nearly all CRC cases, plays a crucial role in CSC-related processes such as proliferation, epithelial-mesenchymal transition (EMT), and metastasis. In this study, we demonstrate that HUWE1 plays a critical regulator of Wnt/β-catenin signaling, similar to the β-catenin destruction complex. Under conditions of β-catenin destruction complex inactivation, most HUWE1 directly interacts with and ubiquitinates β-catenin. Conversely, when the destruction complex is active, HUWE1 targets upstream proteins for ubiquitination, thereby regulating Wnt/β-catenin signaling. This highlights HUWE1 as a pivotal regulator of Wnt/β-catenin signaling, particularly in CRC cases characterized by frequent APC mutations. Our findings further show that HUWE1 loss in CRC cells stabilizes β-catenin, enhancing CSC traits and promoting EMT. Additionally, HUWE1 depletion leads to excessive mitochondrial biogenesis, which contributes to drug resistance by supplying significant ATP levels to ATP-binding cassette (ABC) transporters. In conclusion, this study uncovers a previously unrecognized role of HUWE1 in regulating Wnt/β-catenin signaling and its impact on CRC. These insights may aid in identifying colorectal CSCs and developing targeted therapeutic strategies.","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":"11 1","pages":"424"},"PeriodicalIF":7.0,"publicationDate":"2025-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12500962/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145238135","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}

引用次数: 0

Increased efficacy of PARP inhibitors against cisplatin-sensitive and -resistant ovarian cancer cells mediated via ATR and ATM inhibition. PARP抑制剂对通过ATR和ATM抑制介导的顺铂敏感和耐药卵巢癌细胞的疗效增加。

IF 7 2区生物学

Cell Death Discovery Pub Date : 2025-10-06 DOI: 10.1038/s41420-025-02740-1

Philipp König, Leon Bade, Julia Maria Eichhorn, Helena Skalski, Jindrich Cinatl, Martin Michaelis, Gerd Bendas

{"title":"Increased efficacy of PARP inhibitors against cisplatin-sensitive and -resistant ovarian cancer cells mediated via ATR and ATM inhibition.","authors":"Philipp König, Leon Bade, Julia Maria Eichhorn, Helena Skalski, Jindrich Cinatl, Martin Michaelis, Gerd Bendas","doi":"10.1038/s41420-025-02740-1","DOIUrl":"10.1038/s41420-025-02740-1","url":null,"abstract":"PARP inhibitors (PARPi) are approved for the treatment of platinum-based therapy-responsive ovarian cancer. However, this severely restricts their therapeutic potential, since there is only limited knowledge on the efficacy of PARPi in platinum drug-resistant ovarian cancer cells. Here, we studied three approved PARPi, niraparib, olaparib, and rucaparib in three ovarian cancer cell lines and their cisplatin-resistant sublines. Complex response profiles demonstrated that cisplatin resistance was not consistently associated with cross-resistance to PARPi. The combination of PARPi with inhibitors of relevant DNA damage response kinases which are potentially involved in PARPi resistance, such as ATR, ATM, CHK1, and WEE1 again resulted in complex activity patterns, but also identified ATR and ATM as the most promising targets for increasing PARPi activity. Cell adhesion-mediated resistance via collagen I is known to mediate cisplatin resistance. Here, we show that collagen I can also mediate PARPi resistance, which can also be tackled by ATR and ATM inhibition in cisplatin-sensitive and cisplatin-resistant ovarian cancer cell lines. In conclusion, our findings revealed complex, cell line-specific PARPi response profiles. This complexity is in line with other studies investigating drug-resistant cancer cell lines and with the complex evolutionary processes in tumors from cancer patients. Notably, cisplatin resistance was not directly correlated with PARPi resistance, and ATM and ATR inhibitors can increase PARPi activity against cisplatin-sensitive and -resistant ovarian cancer cells. Moreover, we demonstrated for the first time that cell adhesion-mediated resistance can contribute to PARPi resistance, which can also be alleviated by ATR and ATM.","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":"11 1","pages":"438"},"PeriodicalIF":7.0,"publicationDate":"2025-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12501025/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145238193","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}

引用次数: 0

BRPF1 in cancer epigenetics: a key regulator of histone acetylation and a promising therapeutic target. BRPF1在癌症表观遗传学中的作用：组蛋白乙酰化的关键调控因子和有希望的治疗靶点。

IF 7 2区生物学

Cell Death Discovery Pub Date : 2025-10-06 DOI: 10.1038/s41420-025-02730-3

Elena Alexandrova, Roberto Parisi, Marharyta Smal, Domenico Di Rosa, Alfonso Carleo, Elena Orlando, Carmela Veneri, Viola Melone, Annamaria Salvati, Roberta Tarallo, Giovanni Nassa, Alessandro Weisz, Francesca Rizzo

{"title":"BRPF1 in cancer epigenetics: a key regulator of histone acetylation and a promising therapeutic target.","authors":"Elena Alexandrova, Roberto Parisi, Marharyta Smal, Domenico Di Rosa, Alfonso Carleo, Elena Orlando, Carmela Veneri, Viola Melone, Annamaria Salvati, Roberta Tarallo, Giovanni Nassa, Alessandro Weisz, Francesca Rizzo","doi":"10.1038/s41420-025-02730-3","DOIUrl":"10.1038/s41420-025-02730-3","url":null,"abstract":"Bromodomain and PHD finger-containing protein 1 (BRPF1) is an essential component of histone acetyltransferase complexes, where it acts as a scaffold to facilitate their assembly and enzymatic activity, thereby playing a key role in chromatin remodeling and transcriptional regulation. Emerging evidence indicates that BRPF1 is frequently dysregulated in cancer and contributes to tumorigenesis by modulating key oncogenic pathways. Its overexpression has been associated with poor prognosis in multiple malignancies, highlighting its relevance as a candidate for targeted therapy. Specifically, BRPF1 is particularly implicated in cancers of gastrointestinal and genitourinary systems, as well as in brain, skin, breast, and hematological tumors. The development of selective BRPF1 bromodomain inhibitors has opened new therapeutic avenues, with preclinical models showing notable anticancer effects. Moreover, combinatorial strategies involving BRPF1 inhibitors and other targeted therapies have shown promise in enhancing treatment efficacy. This review provides a comprehensive overview of BRPF1 structure and function, its oncogenic role, and the therapeutic targeting strategies. We also examined current advancements in drug development, highlighting the challenges in BRPF1 inhibition, and proposed future research directions to elucidate its role in cancer epigenetics and translate these insights into improved clinical outcomes.","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":"11 1","pages":"435"},"PeriodicalIF":7.0,"publicationDate":"2025-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12501302/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145238220","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}

引用次数: 0

Combination of HDAC inhibitor and PI3K inhibitor suppresses autophagy and induces apoptosis via cytoplasmic IκBα stabilization in p53-mutant diffuse large B-cell lymphoma. HDAC抑制剂和PI3K抑制剂联用抑制p53突变型弥漫性大b细胞淋巴瘤自噬，通过胞质IκBα稳定诱导细胞凋亡。

IF 7 2区生物学

Cell Death Discovery Pub Date : 2025-10-06 DOI: 10.1038/s41420-025-02756-7

Jingwei Yao, Mengqi Li, Yuelong Jiang, Nanye Yao, Yating Liu, Liemei Lv, Yuchen Li, Jiewen Huang, Jie Zha, Bing Xu

{"title":"Combination of HDAC inhibitor and PI3K inhibitor suppresses autophagy and induces apoptosis via cytoplasmic IκBα stabilization in p53-mutant diffuse large B-cell lymphoma.","authors":"Jingwei Yao, Mengqi Li, Yuelong Jiang, Nanye Yao, Yating Liu, Liemei Lv, Yuchen Li, Jiewen Huang, Jie Zha, Bing Xu","doi":"10.1038/s41420-025-02756-7","DOIUrl":"10.1038/s41420-025-02756-7","url":null,"abstract":"p53-mutant (p53-MUT) diffuse large B-cell lymphoma (p53+ DLBCL) remains a treatment-refractory DLBCL subtype lacking effective therapies. In this study, we systematically validated the synergistic therapeutic potential of HDAC inhibitor chidamide and PI3K inhibitor duvelisib in p53+ DLBCL through cellular models, in vivo experiments, and clinical samples. The combination regimen demonstrated robust induction of apoptosis across multiple p53+ DLBCL cell lines and primary clinical samples. Furthermore, it effectively reduced tumor burden in xenograft mouse models and prolonged overall survival. To elucidate the underlying mechanisms, clinical DLBCL tumor specimens from patients with p53-mutated and p53-wild-type genotypes, as well as p53+ DLBCL cell line samples before and after treatment with chidamide and duvelisib, were collected for RNA-seq analysis. Mechanistically, the combination stabilized IκBα via dual inhibition of PI3Kδ and HDAC2, thereby suppressing NF-κB-p65 phosphorylation and subsequent nuclear translocation, concurrently inhibiting autophagy. These pathway disruptions collectively led to tumor proliferation arrest and potentiation of apoptosis. Specifically, duvelisib inhibited IKK phosphorylation to prevent IκBα degradation, while chidamide enhanced acetylation of histone H1.5 by targeting lysine residues at positions K67 and K93. This acetylation promoted histone H1.5-IκBα interactions, further stabilizing IκBα and attenuating p65 nuclear trafficking. Our findings identify a novel and potent therapeutic strategy for p53+ DLBCL, warranting clinical translation.","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":"11 1","pages":"445"},"PeriodicalIF":7.0,"publicationDate":"2025-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12501026/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145238139","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}

引用次数: 0