Apoptosis最新文献

{"title":"The GATA3-RFPL3-ASK1 axis suppresses breast cancer growth and lung metastasis","authors":"Kang Li,&nbsp;Chang Liu,&nbsp;Jun-Hui Yin,&nbsp;Yu-Ting He,&nbsp;Zhi-Zhi Xu,&nbsp;Wen-Jing Zhang,&nbsp;Jian-Qi Wang,&nbsp;Lu-Yao Hou,&nbsp;Jing Feng,&nbsp;Le-Min Lin,&nbsp;Xiu-Qing Duan,&nbsp;Yi Zhou,&nbsp;Liang Ji","doi":"10.1007/s10495-026-02335-w","DOIUrl":"10.1007/s10495-026-02335-w","url":null,"abstract":"<div><p>Despite the great improvements made in its clinical management during the past decades, breast cancer remains a challenge with considerably high morbidity and mortality. Further efforts to explore new biomarkers with promising clinical potential are still needed nowadays. Collectively, our findings reveal the GATA3-RFPL3-ASK1 axis as a novel tumor-suppressive pathway in breast cancer. Mechanistically, GATA3 transcriptionally activates RFPL3 by directly binding to its promoter. Subsequently, RFPL3 stabilizes and activates ASK1 via K63-linked polyubiquitination, which in turn activates the ASK1-JNK/p38 signaling cascade. The signaling cascade induces apoptosis. Concurrently, this signaling cascade inhibits epithelial-mesenchymal transition (EMT) and invadopodia formation, thereby effectively inhibiting cell migration and invasion. The GATA3-RFPL3-ASK1 axis suppresses breast cancer growth and lung metastasis in vivo.</p></div>","PeriodicalId":8062,"journal":{"name":"Apoptosis","volume":"31 4","pages":""},"PeriodicalIF":8.1,"publicationDate":"2026-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147715683","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Relationship between different modes of death and premature ovarian insufficiency: a literature review","authors":"Huihui Li,&nbsp;Ruotong Ju,&nbsp;Puhua zhang,&nbsp;Chenyu Jia,&nbsp;Tingting Xue,&nbsp;Shu Wang,&nbsp;Xinyu Zhu,&nbsp;Ruixiang Zhu,&nbsp;Jiali Luo,&nbsp;Xuan Jing,&nbsp;Xiangrong Cui","doi":"10.1007/s10495-026-02337-8","DOIUrl":"10.1007/s10495-026-02337-8","url":null,"abstract":"<div><p>Early-onset ovarian insufficiency (POI) is a heterogeneous disorder characterized by complex etiology and the involvement of diverse programmed cell death modalities. This review aims to systematically elucidate the molecular mechanisms underlying programmed cell death in the pathogenesis of POI, with an emphasis on regulatory signaling networks and the dynamic switching of cell death modalities under distinct etiological contexts. We summarize the roles of key programmed cell death pathways—including apoptosis, pyroptosis, ferroptosis, necroptosis, and autophagic cell death—in the onset and progression of POI. In addition, potential therapeutic strategies targeting dysregulated cell death processes are briefly discussed.</p></div>","PeriodicalId":8062,"journal":{"name":"Apoptosis","volume":"31 4","pages":""},"PeriodicalIF":8.1,"publicationDate":"2026-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147697433","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Kaempferol protects melanocytes from ferroptosis by modulating the NF-κB/PTGS2 signaling axis in vitiligo","authors":"Xuqing Xu,&nbsp;Zixian Lei,&nbsp;Wen Hu,&nbsp;Hongjuan Wang,&nbsp;Fang Xiang,&nbsp;Yuan Ding,&nbsp;Xiaojing Kang","doi":"10.1007/s10495-026-02334-x","DOIUrl":"10.1007/s10495-026-02334-x","url":null,"abstract":"<div><p>Oxidative stress-induced ferroptosis is increasingly recognized as an important contributor to melanocyte destruction in vitiligo; however, the specific upstream signaling networks linking inflammatory signaling to ferroptosis susceptibility remain incompletely defined. Kaempferol, a natural flavonoid and key bioactive constituent of the traditional herb <i>Vernonia anthelmintica</i> (L.) Willd., possesses antioxidant and anti-inflammatory properties, yet its potential to mitigate melanocyte ferroptosis warrants investigation. We established an RSL3 (Ras-selective lethal 3)-induced ferroptosis model in primary human melanocytes and employed a multi-dimensional approach integrating transcriptomic profiling, network pharmacology, molecular docking, and immunofluorescence analysis. Clinical relevance was validated using lesional skin tissues from vitiligo patients. RSL3 challenge triggered canonical ferroptosis features, including lethal lipid peroxidation, glutathione depletion, and characteristic mitochondrial shrinkage, all of which were significantly attenuated by kaempferol. Mechanistically, unbiased transcriptomic and network analyses identified prostaglandin-endoperoxide synthase 2 (PTGS2) as a convergent node associated with both nuclear factor-κB (NF-κB)-driven inflammatory signaling and ferroptosis stress. We found that kaempferol markedly inhibited p65 nuclear translocation, accompanied by suppression of PTGS2 transcription. Notably, pharmacological inhibition of NF-κB using BAY 11-7082 phenocopied the anti-ferroptosis efficacy of kaempferol, supporting the functional involvement of this signaling axis. Furthermore, clinical analyses revealed aberrant activation of the NF-κB/PTGS2 pathway concomitant with ferroptosis signatures in vitiligo lesions. Our findings identify ferroptosis as a critical mechanism of melanocyte injury and delineate an NF-κB/PTGS2-associated signaling framework linking oxidative stress, inflammatory activation, and ferroptosis damage. By modulating this stress-responsive axis, kaempferol confers robust protection against ferroptosis melanocyte injury, highlighting its potential relevance as a ferroptosis-modulating strategy.</p></div>","PeriodicalId":8062,"journal":{"name":"Apoptosis","volume":"31 4","pages":""},"PeriodicalIF":8.1,"publicationDate":"2026-04-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147687663","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dynamic collaboration between mitochondria and organelles: mechanisms, functions, and disease implications","authors":"Bin Shao,&nbsp;Yifeng Zeng,&nbsp;Jian Ju","doi":"10.1007/s10495-026-02338-7","DOIUrl":"10.1007/s10495-026-02338-7","url":null,"abstract":"<div><p>In recent years, numerous studies have revealed that dysregulation of mitochondria-organelle interactions is a common feature underlying various pathological processes and pathogen infections. For instance, in Alzheimer's disease (AD), dysfunction of mitochondrial-associated ER membranes (MAMs) leads to calcium overload and oxidative stress, while cancer cells enhance glycolysis by remodeling mitochondria-Golgi interactions. Targeting these key interacting nodes has shown significant therapeutic potential. Although technological advances have uncovered some underlying mechanisms, the spatiotemporal dynamics, tissue specificity, and causal role of organelle interactions in diseases remain unclear. In-depth understanding of these collaborative networks will provide new targets for the treatment of cancer, metabolic syndrome, and neurodegenerative diseases, and also create novel possibilities for elucidating pathogen-host interaction mechanisms and developing anti-infective therapies. Given the importance of dynamic mitochondria-organelle collaboration in disease treatment, this review first focuses on analyzing the molecular mechanisms underlying this crosstalk. Building on this, the dysregulation of mitochondria-organelle collaboration in diseases is discussed in depth, with a particular focus on cancer, cardiovascular diseases, metabolic syndrome, and neurodegenerative diseases. Finally, the potential therapeutic strategies targeting organelle interactions are summarized and analyzed. In conclusion, the information in this manuscript offers a new way to think about and treat several serious illnesses.</p></div>","PeriodicalId":8062,"journal":{"name":"Apoptosis","volume":"31 4","pages":""},"PeriodicalIF":8.1,"publicationDate":"2026-04-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147687716","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pyroptosis as a double-edged sword in colorectal cancer: Molecular mechanisms and therapeutic opportunities","authors":"Han-Xi Zhang,&nbsp;Wen-Jing Xu,&nbsp;Yi-Xin Jiang,&nbsp;Lu Li,&nbsp;Bai-Yu Chen,&nbsp;Meng-Yao Cheng,&nbsp;Meng-Yuan Hao,&nbsp;Hang-Shen Han,&nbsp;Hong-Jie Li,&nbsp;Yan-Ge Li,&nbsp;Dong-Dong Wu","doi":"10.1007/s10495-026-02309-y","DOIUrl":"10.1007/s10495-026-02309-y","url":null,"abstract":"<div><p>Colorectal cancer (CRC) is the third most prevalent malignancy globally, with its incidence and mortality rates exhibiting a consistent upward trend. It is commonly diagnosed at an advanced stage, constraining the available therapeutic strategies. Despite extensive research on CRC development and treatment, its specific pathological mechanisms are still not fully understood, and existing therapies face limitations. As one subtype of programmed cell death (PCD), pyroptosis is increasingly connected to complex interactions in cancer. Driven by the gasdermin (GSDM) family, pyroptosis plays context-dependent dual roles in CRC: it can promote tumorigenesis via sustained chronic inflammation and an immunosuppressive tumor microenvironment (TME), or suppress tumors through direct cancer cell killing and antitumor immunity activation. To build on prior work, this review systematically integrates its core molecular mechanisms, context-dependent dual roles, pathway crosstalk (apoptosis, ferroptosis, PANoptosis), and multilevel regulatory networks (gut microbiota, metabolism, epigenetics, non-coding RNAs (ncRNAs)), which have rarely been synthesized cohesively. We explore the clinical implications, with a focus on pyroptosis-based therapeutic strategies (chemotherapy sensitization, natural compounds, nanomedicines, photodynamic therapy (PDT)/sonodynamic therapy (SDT)) and their translational potential, while addressing the critical challenge of balancing their dual effects—an aspect that has not been fully elaborated in previous reviews.</p></div>","PeriodicalId":8062,"journal":{"name":"Apoptosis","volume":"31 4","pages":""},"PeriodicalIF":8.1,"publicationDate":"2026-04-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147662033","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeting VDAC1 to protect against mitochondria-linked cell death pathways: apoptosis, pyroptosis, ferroptosis, and associated diseases","authors":"A. Shteinfer-Kuzmine,&nbsp;A. Karunanithi Nivedita,&nbsp;M. Santhanam,&nbsp;S. Trishna,&nbsp;R. W. Swerdlow,&nbsp;J. Pan,&nbsp;V. Shoshan-Barmatz","doi":"10.1007/s10495-025-02217-7","DOIUrl":"10.1007/s10495-025-02217-7","url":null,"abstract":"<div><p>The pathways of programmed cell death (PCD), including apoptosis, pyroptosis, and ferroptosis, are interconnected. They can be activated simultaneously within tissues or cell lines and are often associated with various diseases. Thus, identifying a common player and inhibitor targeting several PCD types is essential. Here, we show that overexpression and oligomerization of the mitochondrial gatekeeper voltage-dependent anion channel 1 (VDAC1) is involved in apoptosis, pyroptosis, and ferroptosis, and specific VDAC1 oligomerization inhibitors, VBIT-4 and VBIT-12, prevented multiple forms of PCD triggered by various stimuli. In addition, they mitigated mitochondrial dysfunction, reduced reactive oxygen species production and intracellular Ca²⁺ levels, preserved mitochondrial-associated hexokinase, and inhibited assembly/activation of the NLRP3 inflammasome. In Alzheimer’s disease and inflammatory bowel disease mouse models, VBIT-4 and VBIT-12, respectively, protected against apoptosis, pyroptosis, ferroptosis, and disease-associated pathologies. Thus, we show that VDAC1 oligomerization represents a prime target for VBIT-4 and VBIT-12 that can simultaneously inhibit various PCD forms and diseases associated with enhanced PCD and/or inflammation.</p></div>","PeriodicalId":8062,"journal":{"name":"Apoptosis","volume":"31 4","pages":""},"PeriodicalIF":8.1,"publicationDate":"2026-04-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s10495-025-02217-7.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147642906","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":"SIRT1-regulated mitophagy mitigates lipotoxicity-induced ferroptosis in diabetic kidney disease","authors":"Yingchun Jian,&nbsp;Yongqin Zeng,&nbsp;Zhengdi Wang,&nbsp;Xingyan Zhou,&nbsp;Haiping Zhang,&nbsp;Dan Liang,&nbsp;Rui Yan","doi":"10.1007/s10495-026-02267-5","DOIUrl":"10.1007/s10495-026-02267-5","url":null,"abstract":"<div><p>Diabetic kidney disease (DKD) is characterized by renal lipid deposition, andlipotoxicity-induced ferroptosis plays a pivotal role in its progression. This study aimed to elucidate the regulatory mechanism of silent information regulator 1 (SIRT1) in lipotoxicity-induced ferroptosis in DKD using clinical samples, animal models, and cellular experiments. Renal tissues from DKD patients and non-diabetic controls were collected for pathological and molecular analyses. DKD mouse model was established by combining a high-fat diet (HFD) with streptozotocin (STZ) injection. Human renal proximal tubular epithelial cells (HK-2) were exposed to palmitic acid/high glucose (PA/HG) to mimic lipotoxic sress. SIRT1 overexpression or knockdown was achieved using lentiviral vectors. Mitophagy was evaluated by Western blot, qPCR, and immunohistochemistry (IHC), and transmission electron microscopy (TEM), focusing on the expression of PINK1, Parkin, LC3B, and P62. Ferroptosis was assessed by detecting the expression of glutathione peroxidase 4 (GPX4), xCT, Ferritin, as well as the levels of malondialdehyde (MDA), and reactive oxygen species (ROS), alongside TEM observations of ferroptotic mitochondrial alterations. The mitophagy inhibitor Mdivi-1 and ferroptosis inhibitor Ferrostatin-1 (Fer-1) were used for mechanistic validation. In renal tubules of DKD patients and HFD/STZ-induced DKD mice, lipid droplet membrane protein (Perilipin-2) expression and lipid deposition were markedly elevated, while SIRT1 expression was significantly reduced and negatively correlated with lipid deposition (<i>P</i> &lt; 0.05). PA/HG treated HK-2 cells reproduced these features. SIRT1 deficiency impaired mitophagy, as evidenced by reduced expression of PINK1, Parkin, and LC3B, increased P62 levels (<i>P</i> &lt; 0.05), and TEM revealed mitochondrial swelling with decreased autophagosomes. Furthermore, SIRT1 knockdown exacerbated ferroptosis, characterized by reduced GPX4, xCT, and Ferritin expression, increased MDA and ROS levels (<i>P</i> &lt; 0.05), and mitochondrial pyknosis with loss of cristae. Conversely, SIRT1 overexpression restored mitophagy activity and alleviated ferroptosis (<i>P</i> &lt; 0.05). The protective effect of SIRT1 overexpression against PA-induced ferroptosis was abolished by Mdivi-1, while Fer-1 partially rescued SIRT1 downregulation-induced renal fibrosis (<i>P</i> &lt; 0.05). SIRT1 attenuates lipotoxicity-induced ferroptosis in renal tubular epithelial cells by promoting mitophagy, thereby mitigating DKD progression. These findings suggest that SIRT1-mediated mitophagy may represent a potential therapeutic target for DKD.</p></div>","PeriodicalId":8062,"journal":{"name":"Apoptosis","volume":"31 4","pages":""},"PeriodicalIF":8.1,"publicationDate":"2026-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147626971","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"NUFIP1-engineered exosomes modulate propofol-induced neurotoxicity in neonatal rats via the ERS apoptotic pathway","authors":"Pengyue Zhao,&nbsp;Yang Yan,&nbsp;Bin Lan,&nbsp;Xingpeng Yang,&nbsp;Yizhao Ma,&nbsp;Yichen Bao,&nbsp;Lin Qi,&nbsp;Xiaohui Du,&nbsp;Songyan Li,&nbsp;Wen Sun","doi":"10.1007/s10495-026-02326-x","DOIUrl":"10.1007/s10495-026-02326-x","url":null,"abstract":"<div><p>Early-life exposure to general anesthetics, particularly propofol, elevates the risk of neurodevelopmental impairment and cognitive sequelae in pediatric populations, representing a pivotal concern in translational neuroanesthesiology. Although preclinical studies have linked propofol to increased developmental neurotoxicity, the underlying molecular mechanisms remain elusive. Our previous work established that nuclear fragile X mental retardation-interacting protein 1 (NUFIP1)-engineered exosomes from human umbilical cord mesenchymal stem cells could mitigate propofol-induced neurotoxicity and neuronal apoptosis in neonatal rats during a critical postnatal window of synaptogenesis (postnatal days 7–14). The present study provides the first mechanistic insights by performing transcriptomic profiling to link this neuroprotection to the endoplasmic reticulum stress (ERS) apoptotic pathway. Importantly, we directly validated key ERS/apoptosis markers and functionally confirmed the pathway’s role through pharmacological rescue experiments with Salubrinal. In conclusion, NUFIP1-engineered exosomes regulate propofol-induced nerve injury through the ERS apoptotic pathway, offering novel mechanistic insights with potential implications for addressing pediatric neurodevelopmental impairments.</p></div>","PeriodicalId":8062,"journal":{"name":"Apoptosis","volume":"31 4","pages":""},"PeriodicalIF":8.1,"publicationDate":"2026-04-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147626968","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Helicobacter pylori activates the TRAF1/OASL/ZBP1-PANoptosome pathway to induce PANoptosis in the gastric mucosa","authors":"Minglin Zhang,&nbsp;Xueer Yang,&nbsp;Jie Xie,&nbsp;Ting Cai,&nbsp;Xuelin Zhao,&nbsp;Xiaoming Liu,&nbsp;Fen Wang","doi":"10.1007/s10495-026-02321-2","DOIUrl":"10.1007/s10495-026-02321-2","url":null,"abstract":"<div><p><i>Helicobacter pylori</i> (<i>H. pylori</i>) has been identified as a pathogenic factor in gastric cancer (GC). Building on our previous findings that VacA upregulates TRAF1, which in turn transcriptionally activates OASL, we explored the role of this TRAF1-OASL-PANoptosis axis in GC using clinical samples, cell lines, and mouse models. Functional assays (CCK-8, colony formation, migration, invasion, TUNEL) demonstrated that TRAF1 promotes GC cell proliferation, migration, and invasion via OASL, while suppressing apoptosis. RNA-seq revealed that upregulation of TRAF1 and OASL, combined with <i>H. pylori</i> infection in gastric epithelial cells, enriched pathways associated with PANoptosis. Rescue experiments showed that TRAF1 knockdown increased PANoptosis, and this increase was attenuated by the pan-caspase inhibitor Z-VAD-FMK, whereas subsequent OASL overexpression reversed the suppression of PANoptosis caused by TRAF1 knockdown, whereas LPS further induced PANoptosis. Both in vitro and in vivo models confirmed that <i>H. pylori</i> infection triggers PANoptosis. Co-Immunoprecipitation assays uncovered a protein interaction between OASL and the ZBP1-PANoptosome. Critically, under <i>H. pylori</i> infection conditions, OASL overexpression rescued the PANoptosis suppressed by TRAF1 knockdown in gastric epithelial cells. This study demonstrates that <i>H. pylori</i> infection induces PANoptosis, and defines a pathway wherein TRAF1 promotes PANoptosis by regulating OASL-mediated activation of the ZBP1-PANoptosome. Our findings reveal a novel, context-dependent duality of the TRAF1/OASL axis: it promotes PANoptosis, contributing to mucosal damage during the precancerous inflammatory stage, yet in established GC, this axis appears to suppress PANoptosis, facilitating tumor progression. These insights provide a theoretical foundation for targeting this pathway in treating <i>H. pylori</i>-associated gastritis-cancer progression.</p></div>","PeriodicalId":8062,"journal":{"name":"Apoptosis","volume":"31 4","pages":""},"PeriodicalIF":8.1,"publicationDate":"2026-04-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147626974","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"MUDENG, a component of adaptor complex 5, mediates TRAIL- and TMZ-triggered apoptosis in glioblastoma (GBM) via multiple pathways","authors":"Juhyun Shin,&nbsp;Yoon-Mi Lee,&nbsp;SooHyun Jung,&nbsp;Sumin Han,&nbsp;Arti Nile,&nbsp;Su-Jin Kim,&nbsp;Sang-Won Lee,&nbsp;Jae-wook Oh","doi":"10.1007/s10495-026-02293-3","DOIUrl":"10.1007/s10495-026-02293-3","url":null,"abstract":"<div><p>Glioblastoma (GBM) is one of the most aggressive and treatment-refractory brain tumors. Temozolomide (TMZ) remains the standard chemotherapeutic agent but is frequently compromised by DNA-repair mechanisms, whereas tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) induces apoptosis only in a subset of tumors due to strong intrinsic resistance. Here, we identify the Mu-2-related death-inducing gene (MUDENG/MuD) as the µ-subunit of adaptor protein complex 5 (AP5M1). TurboID-based proximity labeling revealed reproducible interactions with AP5B1 and AP5M1 subunits, as well as additional associations with AP1–3 complexes and nuclear proteins involved in cell-cycle regulation. These findings establish MuD as a multifunctional component of the AP5 complex that modulates cell-fate signaling in a context-dependent manner. Using MuD-mutant GBM cell lines, we demonstrate that MuD suppresses TRAIL-induced apoptosis by interfering with extrinsic and intrinsic pathways downstream of Bid, whereas it promotes TMZ-induced cytotoxicity through p53-dependent cell-cycle control and DNA-damage responses. Gene set enrichment analysis (GSEA) and functional profiling further revealed distinct MuD-associated interactomes linked to receptor endocytosis and genotoxic-stress pathways. Together, these results uncover opposing roles of MuD in TRAIL- and TMZ-mediated cell death, with MuD suppressing apoptotic signaling in response to TRAIL while modulating p53-dependent genotoxic stress responses that influence TMZ-induced cytotoxicity in glioblastoma.</p></div>","PeriodicalId":8062,"journal":{"name":"Apoptosis","volume":"31 4","pages":""},"PeriodicalIF":8.1,"publicationDate":"2026-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147580199","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}