Cell Death Discovery最新文献

{"title":"Cuproptosis and cuproptosis-related cell death and genes: mechanistic links to spermatogenic cell death.","authors":"Junjun Li, Nihong Li, Hong Wang, Bin Li, Xinyi Tang, Yanxin Guan, Fang Yang, Guangsen Li, Liang Dong, Renbin Yuan, Xujun Yu","doi":"10.1038/s41420-025-02553-2","DOIUrl":"10.1038/s41420-025-02553-2","url":null,"abstract":"<p><p>Spermatogenesis, which is regulated by multiple cell death mechanisms, is an extremely complex process. The significance of cell death during spermatogenesis is a topic of interest because of its potential medical implications. Cuproptosis is a new mechanism of cell death discovered in recent years, and recent studies have preliminarily confirmed that cuproptosis is involved in the process of spermatogenic cell death, but its specific role in the process of spermatogenic cell death is still unclear. In this review, the mechanisms of spermatogenic cell death associated with cuproptosis and the effects of key genes of cuproptosis on spermatogenesis are discussed together with some new perspectives for the study of spermatogenic cell death.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":"11 1","pages":"274"},"PeriodicalIF":6.1,"publicationDate":"2025-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12152130/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144265335","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":"CYPD limits HR⁺ mammary carcinogenesis in mice.","authors":"Aitziber Buqué, Manuel Beltrán-Visiedo, Ai Sato, Claudia Galassi, Giulia Petroni, Lorenzo Galluzzi","doi":"10.1038/s41420-025-02555-0","DOIUrl":"10.1038/s41420-025-02555-0","url":null,"abstract":"<p><p>Mitochondrial permeability transition (MPT)-driven necrosis and necroptosis are regulated variants of cell death that can drive inflammation or even promote antigen-specific immune responses. In oncological settings, indolent inflammatory reactions have been consistently associated with accelerated disease progression and resistance to treatment. Conversely, adaptive immune responses specific for tumor-associated antigens are generally restraining tumor development and contribute to treatment sensitivity. Here, we harnessed female C57BL/6J mice lacking key regulators of MPT-driven necrosis and necroptosis to investigate whether whole-body defects in these pathways would influence mammary carcinogenesis as driven by subcutaneous slow-release medroxyprogesterone acetate (MPA, M) pellets plus orally administered 7,12-dimethylbenz[a]anthracene (DMBA, D), an in vivo model that recapitulates multiple facets of the biology and immunology of human hormone receptor positive (HR⁺) breast cancer. Our data demonstrate that female mice bearing a whole-body, homozygous deletion in peptidylprolyl isomerase F (Ppif), which encodes a key regulator of MPT-driven necrosis commonly known as CYPD, but not female mice with systemic defects in necroptosis as imposed by the whole body-deletion homozygous of receptor-interacting serine-threonine kinase 3 (Ripk3) or mixed lineage kinase domain like pseudokinase (Mlkl), are more susceptible to M/D-driven carcinogenesis than their wild-type counterparts. These findings point to CYPD as to an oncosuppressive protein that restrains HR⁺ mammary carcinogenesis in mice, at least potentially via MPT-driven necrosis.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":"11 1","pages":"273"},"PeriodicalIF":6.1,"publicationDate":"2025-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12152121/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144265336","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":"Androgen-induced AR-BRD4 transcriptional regulatory complex promotes malignant proliferation of osteosarcoma cells.","authors":"Jia-Ming Tian, Yi-He Dong, Zi Li, Yong Zhou, Jun Huang","doi":"10.1038/s41420-025-02541-6","DOIUrl":"10.1038/s41420-025-02541-6","url":null,"abstract":"<p><p>Osteosarcoma (OS) is deemed as hormone-dependent neoplasm. Here we explored its latent mechanisms governing the interactions between specific molecules and hormones involved in OS progression. Through multiplex IHC analysis in TMA, bioinformatics analysis, and a series of in vitro and in vivo molecular assays, we identified BRD4 and sex steroid receptors were positively expressed in clinical OS tissues, simultaneously BRD4 and AR expression were elevated in the osteoblastic subtype, while ERβ predominated in the fibroblastic subtype. GEO database revealed a positive correlation between BRD4 and AR expression, while no correlation was found with ERβ expression. In vitro studies demonstrated that DHT stimulation resulted in a significant upregulation of AR and BRD4 protein expression, subsequently promoting the proliferation of OS cells. ChIP-sequencing and dual-luciferase reporter assays revealed that DHT treatment increased the distribution of BRD4 on chromatin and its overlap with AR, facilitating the formation of the AR-BRD4 transcriptional regulatory complex, which significantly increased transcription levels of AR target genes, such as PLCB4. Moreover, experiments conducted in nude mice indicated that BRD4 inhibitor, (+)-JQ1 decreased the expression of AR-related genes and inhibited OS cell growth in vivo. In conclusion, elevated expression of BRD4 in OS cells induced by androgens participates in AR-related transcriptional regulatory processes, facilitating the malignant progression of OS.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":"11 1","pages":"272"},"PeriodicalIF":6.1,"publicationDate":"2025-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12152148/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144265334","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 epigenetic regulator UHRF1 attenuates renal fibrosis and retains transcription factor Krüppel-like factor 15 expression.","authors":"Yulu Gu, Shiqi Lv, Xinhui Huang, Jialin Wang, Yulin Wang, Han Zhang, Ziyan Shen, Jing Chen, Cheng Zhu, Di Zhang, Xiaoqiang Ding, Xiaoyan Zhang","doi":"10.1038/s41420-025-02549-y","DOIUrl":"10.1038/s41420-025-02549-y","url":null,"abstract":"<p><p>Aberrant DNA methylation modification is well-known to be involved in renal fibrogenesis. As a critical cooperator in DNA methyltransferase 1 (DNMT1)-mediated maintenance of DNA methylation, the role of ubiquitin-like containing PHD and RING finger domains 1 (UHRF1) in renal fibrosis remains unknown. Here, upregulation of UHRF1 is observed in activated renal fibroblasts. Fibroblasts-specific depletion of UHRF1 reduces fibrotic lesions in both unilateral ureter obstruction- and unilateral renal ischemia-reperfusion injury-induced murine models of kidney fibrosis. Through Reduced Representation Bisulfite Sequencing, Krüppel-like factor 15 (KLF15) is screened and further verified as the target methylated gene of UHRF1 and responsible for fibroblasts activation. Moreover, UHRF1 induces KLF15 methylation through interacting with DNMT1. Genetic depletion of UHRF1 or pharmacological inhibition of such interaction decreases KLF15 methylation levels and restores its expression, resulting in reduced renal fibroblasts activation and kidney fibrosis. Collectively, these results suggest that UHRF1 may be a promising target for mitigating renal fibrosis.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":"11 1","pages":"270"},"PeriodicalIF":6.1,"publicationDate":"2025-06-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12149316/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144257455","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":"LMNB2-mediated high PD-L1 transcription triggers the immune escape of hepatocellular carcinoma.","authors":"Yuxuan Li, Jie Zhu, Fengguang Zhai, Yidong Ge, Ziqing Zhan, Shuyan Wang, Lili Kong, Jianan Zhao, Lecheng Hu, Siyuan Wang, Jiaxin Shi, Jianing Mao, Zongdong Yu, Haoyun Wang, Jiabei Jin, Mengxiang Zhao, Hong Li, Xiaofeng Jin","doi":"10.1038/s41420-025-02540-7","DOIUrl":"10.1038/s41420-025-02540-7","url":null,"abstract":"<p><p>While immune checkpoint inhibitors targeting programmed cell death-ligand 1 (PD-L1) demonstrate clinical efficacy in hepatocellular carcinoma (HCC), tumor cells frequently evade immune surveillance through PD-L1 overexpression, a phenomenon whose regulatory mechanisms remain poorly understood. Through integrated analysis of single-cell transcription sequence data, we identified aberrant upregulation of Lamin B2 (LMNB2) specifically in immunotherapy-sensitive HCC patients. Functional characterization revealed that LMNB2 acts as a transcriptional regulator of PD-L1, potentiating immune escape mechanisms in HCC cells during co-culture with Jurkat cells. Notably, we discovered that speckle-type POZ protein (SPOP) directly interacts with LMNB2 to mediate its ubiquitination and proteasomal degradation, thereby maintaining physiological PD-L1 expression levels. Clinically relevant SPOP mutations or reduced SPOP expression impaired this regulatory mechanism, leading to LMNB2 accumulation and subsequent PD-L1 hyperactivation. Importantly, combinatorial targeting of LMNB2 with Atezolizumab (PD-L1 inhibitor) displayed a synergistic effect on suppressing tumor progression both in vitro and in vivo, particularly in HCC models with SPOP mutations or LMNB2 overexpression. These findings unveil a novel ubiquitination-dependent regulatory axis in HCC immune evasion and propose targeted co-inhibition strategies to overcome HCC immunotherapy resistance.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":"11 1","pages":"269"},"PeriodicalIF":6.1,"publicationDate":"2025-06-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12145441/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144246653","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":"GAS6/AXL signaling promotes M2 microglia efferocytosis to alleviate neuroinflammation in sepsis-associated encephalopathy.","authors":"Yuedong Tang, Hanbing Hu, Qiliang Xie, Jie Shen","doi":"10.1038/s41420-025-02507-8","DOIUrl":"10.1038/s41420-025-02507-8","url":null,"abstract":"<p><p>Sepsis-associated encephalopathy (SAE) is a severe complication marked by acute central nervous system (CNS) injury and neuroinflammation. M2 microglia efferocytosis is essential for resolving neuroinflammation, but its regulatory mechanisms remain unclear. This study explored the GAS6/AXL signaling pathway in SAE, hypothesizing its role in enhancing anti-inflammatory responses and efferocytosis. A mouse model of SAE was established via cecal ligation and puncture (CLP), and cognitive impairments were assessed through behavioral tests. Brain tissues and microglia were isolated for RNA sequencing (RNA-Seq) to identify genes associated with the GAS6/AXL pathway. Recombinant GAS6 (rGAS6) protein and an AXL inhibitor were used to examine the pathway's effects on microglial Rac1 activity and functionality. Results demonstrated that GAS6/AXL activation significantly upregulated anti-inflammatory cytokines, enhanced efferocytosis, and suppressed pro-inflammatory responses, improving cognitive outcomes. These findings highlight GAS6/AXL as a critical modulator of microglial functions, providing a promising molecular target for treating SAE. GAS6/AXL Pathway Reduces Neuroinflammation in SAE via Regulation of Anti-Inflammatory and Efferocytic Function in M2 Microglia.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":"11 1","pages":"268"},"PeriodicalIF":6.1,"publicationDate":"2025-06-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12144116/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144246652","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":"ELF1-mediated transactivation of METTL3/YTHDF2 promotes nucleus pulposus cell senescence via m6A-dependent destabilization of E2F3 mRNA in intervertebral disc degeneration.","authors":"Xiao-Wei Liu, Hao-Wei Xu, Shu-Bao Zhang, Yu-Yang Yi, Sheng-Jie Chang, Shan-Jin Wang","doi":"10.1038/s41420-025-02515-8","DOIUrl":"10.1038/s41420-025-02515-8","url":null,"abstract":"<p><p>Intervertebral disc degeneration (IVDD) is a common pathology involving various degenerative diseases of the spine, with nucleus pulposus cell (NPC) senescence playing an important role in its pathogenesis. Transcriptional and epigenetic processes have been increasingly implicated in aging and longevity. E74-like factor 1 (ELF1) is a member of the erythroblast transformation specific family of proteins, which induce gene transcription by binding to gene promoters or enhancer sequences. However, the role of ELF1 in age-related diseases is unclear, with no reports of its involvement in NPC senescence or IVDD. ELF1 expression levels were assessed in human NP samples from IVDD patients, IVDD animal models, and naturally aged NP samples. Adeno-associated virus 5 (AAV5) vector-mediated Elf1 overexpressing mice and Elf1 knockout (KO) mice were used to investigate its role in NPC senescence and IVDD in vivo. The m6A methylase METTL3 and reading protein YTHDF2 were identified as downstream effectors of ELF1 using proteomic sequencing, RNA sequencing, ChIP-seq, promoter prediction, and binding analyses. MepRIP-qPCR, RNA pulldown, and double luciferase point mutation experiments revealed that METTL3 and YTHDF2 can recognize the m6A site on E2F3 mRNA, a key cell cycle gene. Finally, virtual screening techniques and various experiments were used to identify small molecule targets for ELF1 inhibition. ELF1 was found to drive m6A modification changes during NPC aging. The small molecule mycophenolate mofetil (MMF) could successfully target and inhibit ELF1 expression. In senescent NPCs, ELF1 can bind to the METTL3 and YTHDF2 gene promoter regions. Overexpressing METTL3 increased the E2F3 mRNA m6A modification abundance, while YTHDF2 was recruited to recognize this m6A site. This can accelerate the E2F3 mRNA degradation rate and ultimately lead to the onset of G1/S cell cycle arrest in NPC. For the first time, the transcription factor ELF1 has been identified as a novel regulator of NPC senescence and IVDD, which involves the ELF1-METTL3/YTHDF2-m6A-E2F3 axis. MMF, a small molecule designed to inhibit ELF1 and delay NPC senescence, was screened for the first time. This can potentially lead to new epigenetic therapeutic strategies for drug discovery and development for the clinical treatment of IVDD.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":"11 1","pages":"267"},"PeriodicalIF":6.1,"publicationDate":"2025-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12137937/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144224410","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":"FGFR inhibition as a new therapeutic strategy to sensitize glioblastoma stem cells to tumor treating fields.","authors":"Pauline Deshors, Ziad Kheil, Laetitia Ligat, Valerie Gouazé-Andersson, Elizabeth Cohen-Jonathan Moyal","doi":"10.1038/s41420-025-02542-5","DOIUrl":"10.1038/s41420-025-02542-5","url":null,"abstract":"<p><p>Glioblastomas (GBM) are aggressive tumors, which systematically relapse despite standard treatment associating surgery, chemotherapy and radiation therapy. More recently, GBM therapy now includes another therapeutic modality option, Tumor Treating Fields (TTFields) given in combination with Temozolomide (TMZ) following standard treatment. However even with the adjunction of TTFields, GBM remains a lethal disease due to treatment resistance. One of the causes of resistance is the presence of cancer stem cells (GSC) known to be chemo and radioresistant and responsible for tumor regrowth. Studying mechanisms of resistance of GSC to TTFields is thus a major issue to address. Fibroblast Growth Factor Receptors (FGFR) play a major role in numerous processes essential for cancer development, and dysregulation of FGFR signaling has been observed in many cancer types, including GBM. We have previously shown that tyrosine kinase receptor Fibroblast Growth Factor Receptor 1 (FGFR1) controls GBM aggressiveness and GSC radioresistance and that its inhibition leads to radiosensitization through increasing mitotic cell death and microenvironment modulation. Because one of the main mechanisms of action of TTFields is mitotic disturbance and because TTFields act synergistically in vitro with irradiation (IR), we hypothesize that targeting FGFR could sensitize GSC to TTFields. Here we show that, like IR, TTFields significantly decrease GSC growth. Treatment of GSC with pemigatinib (Pem), a FGFR1-3 inhibitor, alters FGFR signalling pathway. We demonstrate that Pem, sensitizes GSC to TTFields by synergistically decreasing their survival and clonogenic ability. Finally, the adjunction of Pem to treatment combining IR and TTFields could sensitize GSC by inducing, in some GSC, a further decrease in the repair of IR-induced DNA damages. Altogether, these results highlight the potential benefits of inhibiting FGFR with the concomitant application of TTFields in the first-line standard GBM treatment to improve patient prognosis.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":"11 1","pages":"265"},"PeriodicalIF":6.1,"publicationDate":"2025-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12137614/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144224412","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":"ERK1-mediated GLYCTK2 phosphorylation promotes fructolysis to sustain glioblastoma survival under glucose deprivation.","authors":"Yingping Li, Fenna Zhang, Fumin Hu, Rui Tong, Yueqi Wen, Guokai Fu, Xueli Bian","doi":"10.1038/s41420-025-02544-3","DOIUrl":"10.1038/s41420-025-02544-3","url":null,"abstract":"<p><p>Metabolic plasticity sustains glioblastoma (GBM) survival under nutrient stress, yet how fructolytic adaptation compensates for glucose deprivation remains unclear. Here, we identify glycerate kinase 2 (GLYCTK2) as a glucose-sensing metabolic checkpoint that maintains GBM cell viability through ERK1-mediated phosphorylation. Mechanistically, glucose deprivation-activated ERK1 phosphorylates GLYCTK2 at serine 220 directly, which prevents STUB1 (ubiquitin E3 ligase) binding, thereby abrogating the ubiquitination and degradation of GLYCTK2. Importantly, Functional studies demonstrated that fructose supplementation rescues glucose deprivation-induced death in wild-type GBM cells, but fails to protect GLYCTK2-depleted cells, establishing GLYCTK2 as the gatekeeper of fructolytic salvage pathways. These findings demonstrate an important mechanism by which GBM cells rewire glucose metabolism to fructose metabolism via phosphorylating and stabilizing GLYCTK2 to maintain GBM cell survival under glucose deprivation condition, underscoring the potential to target GLYCTK2 for the treatment of patients with GBM.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":"11 1","pages":"266"},"PeriodicalIF":6.1,"publicationDate":"2025-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12137673/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144224411","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":"Nesprin-2 contains BH3-like motifs that can promote cell death.","authors":"Hila Zohar, Amit Kessel, Liora Lindenboim, Dang Nguyen, Nir Ben-Tal, Gregg G Gundersen, Howard J Worman, David W Andrews, Reuven Stein","doi":"10.1038/s41420-025-02534-5","DOIUrl":"10.1038/s41420-025-02534-5","url":null,"abstract":"<p><p>BH3-only proteins are a subgroup of the pro-apoptotic Bcl-2 family proteins. They initiate apoptosis by interacting with the multidomain pro- and anti-apoptotic Bcl-2 family proteins. SYNE2 encodes multiple nesprin-2 (Nes2) isoforms of which the most abundant and the largest is the nuclear envelope protein nesprin-2 giant (Nes2G). Nes2G is a component of the nuclear envelope Linker of Nucleoskeleton and Cytoskeleton (LINC) complex that connects the nucleus and the cytoskeleton. Previously, we showed that Nes2 has pro-apoptotic activity. We now show that Nes2G can bind multidomain pro-apoptotic and anti-apoptotic Bcl-2 family proteins and contains two BH3-like motifs near its N- and C-termini. Molecular modeling predicts that these BH3-like motifs have amphipathic α-helix structures and can dock onto the canonical groove of Bax and anti-apoptotic proteins as well as the trigger site of Bax. A chimeric tBid with its BH3 domain replaced with the C-terminal Nes2 BH3-like domain binds to Bax in cells. Furthermore, Nes2 BH3-like motif-containing fragments from the N- and the C-termini bind both pro-apoptotic and anti-apoptotic Bcl-2 proteins and promote cytochrome c release (indicative of apoptosis). Our results suggest that Nes2 acts as a BH3-only protein that regulates apoptosis by binding to the multidomain Bcl-2 family proteins.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":"11 1","pages":"263"},"PeriodicalIF":6.1,"publicationDate":"2025-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12134178/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144215040","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}