Cell Death & Disease最新文献

{"title":"Remodeling of ferroptotic necroinflammation by dexamethasone in acute tubular necrosis.","authors":"Natalie Bethe, Mirela Tmava, Alix Bruneau, Karolin Flade, Benjamin Böhme, Erik Klapproth, Selina Michel, Marlena Nastassja Schlecht, Siyu Xu, Ali El-Armouche, Frank Tacke, Stefan R Bornstein, Wulf Tonnus","doi":"10.1038/s41419-026-09099-w","DOIUrl":"10.1038/s41419-026-09099-w","url":null,"abstract":"<p><p>Ferroptosis, a modality of regulated necrosis caused by iron-dependent lipid peroxidation, has emerged as a key contributor to the pathogenesis of acute tubular necrosis (ATN) - especially in the context of solid organ transplantation. While recent studies have identified hormones as extracellular signals that modulate cellular susceptibility to ferroptosis, their pathophysiological relevance in vivo remains incompletely defined. Here, we investigated the role of dexamethasone, a potent synthetic glucocorticoid previously reported to sensitize cells to ferroptosis, in the context of renal tubular injury. Unexpectedly, we observed a biphasic effect: early sensitization to ferroptosis induced by glutathione depletion was subsequently counteracted by a marked increase in ferroptosis resistance. Mechanistically, we found that dexamethasone reduced availability of ferrous iron via effects of the glucocorticoid receptor 1 (GR1), which also resulted in attenuated renal tubular injury. However, this cytoprotective effect did not translate into improved renal function, as dexamethasone exerted additional ferroptosis-independent effects on innate immune cell recruitment to injured kidneys. Collectively, our findings highlight the highly dynamic nature of the ferroptotic process in which modulatory signals can exert temporally opposing effects. Moreover, they underscore the complex interplay between regulated cell death and innate immune responses in shaping necroinflammation in disease trajectories.</p>","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"17 1","pages":""},"PeriodicalIF":12.2,"publicationDate":"2026-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13373221/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148454748","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Selective killing of ALT-cancer cells by Withaferin-A involves destabilization of Rad51 and disruption of DNA repair.","authors":"Yue Yu, Huayue Zhang, Jia Wang, Jaspreet K Dhanjal, Vidhi Malik, Xiupeng Wang, Sunil C Kaul, Durai Sundar, Renu Wadhwa","doi":"10.1038/s41419-026-09115-z","DOIUrl":"10.1038/s41419-026-09115-z","url":null,"abstract":"<p><p>Alternative lengthening of telomeres (ALT) is a telomerase-independent telomere maintenance mechanism active in a subset of aggressive cancers. Targeting ALT remains a therapeutic challenge due to its complexity and lack of clinically specific inhibitors. Here, we report that the natural compound Withaferin A (Wi-A) selectively impairs ALT cancer cell viability by disrupting Rad51-dependent homologous recombination (HR), a critical pathway for resolving telomeric replication stress and DNA damage in ALT cells. Comparative analysis using isogenic ALT and telomerase-positive cells revealed that Wi-A selectively downregulates PI3K/AKT signaling and induces replication stress, telomeric DNA damage, and DNA repair deficiency in ALT cells. Mechanistically, Wi-A destabilizes the Rad51 nucleoprotein filament and promotes Rad51 degradation via a RFWD3-dependent mechanism localized within ALT-associated PML bodies (APBs). Depletion of either PML or RFWD3 rescues Rad51 stability and reduces sensitivity of ALT cells to Wi-A. Together, these findings uncover a novel mechanism by which Wi-A selectively targets ALT cells through Rad51 destabilization within APBs, highlighting its potential to exploit ALT-specific vulnerabilities in telomere maintenance and DNA repair for therapeutic development.</p>","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":" ","pages":""},"PeriodicalIF":12.2,"publicationDate":"2026-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13649652/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148454810","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"BAP1 deficiency-induced SKA3 promotes clear cell renal cell carcinoma malignant progression by regulating chromosomal instability.","authors":"Yueyang Wang, Chong Lai, Lingling Wang, Jingwen Deng, Zhou Tian, Zhiyong Liang, Honghe Zhang","doi":"10.1038/s41419-026-09076-3","DOIUrl":"10.1038/s41419-026-09076-3","url":null,"abstract":"<p><p>Chromosomal instability (CIN), a hallmark of malignancy, remains poorly understood in clear cell renal cell carcinoma (ccRCC). Here, we identify spindle and kinetochore-associated protein 3 (SKA3) as a critical regulator of CIN in ccRCC. BAP1 loss-of-function mutations, prevalent in ccRCC, drive aberrant SKA3 overexpression. Mechanistically, BAP1 deubiquitinates nuclear receptor co-repressor 1 (NCOR1) to enhance its recruitment to the SKA3 promoter, thereby repressing SKA3 transcription. Additionally, BAP1-mediated histone H2AK119 deubiquitination at the TRIM25 promoter activates the expression of TRIM25, facilitating ubiquitin-proteasome-mediated degradation of SKA3. BAP1 deficiency disrupts both regulatory pathways, leading to aberrant accumulation of SKA3, which fuels CIN and correlates with metastasis progression and poor prognosis. In conclusion, our findings establish dysfunction of the BAP1-SKA3 axis as a molecular driver of CIN in ccRCC and suggest SKA3 as a potential therapeutic target for BAP1-mutant ccRCC.</p>","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":" ","pages":""},"PeriodicalIF":12.2,"publicationDate":"2026-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13649664/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148454798","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CRISPR/Cas9 screen identifies DCAF4 as a novel protector of hepatocellular carcinoma against brachytherapy via stress granule-dependent NRF2 activation.","authors":"Tian Huang, Yanshu He, XinChen Wang, Zhengan Liu, Enqi Qiao, Tong Sun, Junhao Mei, Shipeng Dai, Zhongkai Wang, Cheng Feng, Hengsong Cao, Yiming Wang, Yongxiang Xia, Enyu Liu, Jinhe Guo, Jian Lu","doi":"10.1038/s41419-026-09095-0","DOIUrl":"10.1038/s41419-026-09095-0","url":null,"abstract":"<p><p>Hepatocellular carcinoma (HCC) cells sustain viability and radioresistance by actively countering oxidative stress. Understanding the mechanisms regulating reactive oxygen species (ROS) homeostasis is therefore crucial for developing novel therapies. Using integrated genome-wide CRISPR-Cas9 screening coupled with transcriptomic and metabolomic profiling, we identified DDB1 and CUL4-associated factor 4 (DCAF4) as an essential regulator of oxidative stress resistance in HCC. Mechanistically, DCAF4 functions as a CRL4 E3 ligase adapter that promotes KEAP1 ubiquitination and degradation. Notably, under oxidative stress, cytoplasmic stress granules (SGs) form a localized platform that facilitates the DCAF4-KEAP1 interaction, accelerating KEAP1 degradation and leading to NRF2 activation and upregulation of antioxidant genes. We further identified that the transcription factor XBP1 enhances DCAF4 expression. Targeting this axis, we performed computational screening to identify a small-molecule inhibitor that disrupts the DCAF4-KEAP1 interaction. This compound effectively enhanced brachytherapy (BT) sensitivity and inhibited tumor growth in preclinical HCC models.</p>","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":" ","pages":""},"PeriodicalIF":12.2,"publicationDate":"2026-07-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13594110/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148444712","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The TENT5A-ATXN2 axis modulates germline and somatic cell survival during heat stress.","authors":"Ru-Pin Alicia Chi, Ankit Gupta, Yin Li, Marine Baptissart, Dongwon Lee, Brian N Papas, Marcos Morgan","doi":"10.1038/s41419-026-09086-1","DOIUrl":"10.1038/s41419-026-09086-1","url":null,"abstract":"<p><p>Stress conditions elicit the formation of different kinds of stress granules (SGs). Although male germ cells are particularly sensitive to heat stress, the composition of heat-induced SGs in the testis remains poorly characterized. Here, we show that ATXN2 is a main component of heat-induced SGs in male germ cells and identify a unique population of ATXN2-positive SGs in leptotene and zygotene spermatocytes lacking classical SG markers. The terminal nucleotidyltransferase 5A (TENT5A) is a cytoplasmic poly(A) polymerase that extends the poly(A) tails of mRNAs. Tent5a mRNA expression increases when somatic and germ cells are exposed to 42 °C, but not upon exposure to other stressors. In vitro, TENT5A extends the poly(A) tail of Atxn2 transcripts, stabilizing them while repressing their translation. In heat-stressed testes, TENT5A depletion increases ATXN2-positive granules and reduces apoptosis in late pachytene spermatocytes. Thus, enhanced stress resilience in Tent5a-depleted male germ cells preserves spermatogenesis and rescues fertility following heat exposure.</p>","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":" ","pages":""},"PeriodicalIF":12.2,"publicationDate":"2026-07-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13646263/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148435237","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeting enolase isoenzyme 2 enables precision glycolysis inhibition in VHL-mutant renal cell carcinoma.","authors":"Jiannan Yao, Xiaona Fan, Huixian Xin, Fuhui Wan, Xichen Dong, Qianqian Sun, Xuying Huang, Heshu Liu, Xiangyu Chen, Yanjun Jia, Haili Qian, Tao Wen, Jian Liu","doi":"10.1038/s41419-026-09102-4","DOIUrl":"10.1038/s41419-026-09102-4","url":null,"abstract":"<p><p>Clear cell renal cell carcinoma (ccRCC) exhibits glycolytic addiction due to VHL mutation, making it vulnerable to metabolic intervention. While conventional inhibitors targeting core housekeeping glycolytic enzymes show robust antitumor efficacy, their clinical use is limited by on-target systemic toxicity. Here, we identify enolase 2 (ENO2) as an isoform-specific glycolytic vulnerability specific to VHL-deficient ccRCC. Although ENO2 is physiologically redundant (compensated by ENO1) in normal glycolysis, it becomes essential for sustaining ccRCC malignancy via VHL loss-HIF2α-driven glycolytic flux. Targeting ENO2 specifically suppressed glycolysis in VHL-deficient ccRCC cells, reducing their malignancy and enhancing their response to axitinib, doxorubicin, and gemcitabine. Importantly, pharmacological ENO2 blockade displayed superior tumor selectivity compared to traditional glycolysis inhibitors, effectively eliminating VHL-deficient ccRCC cells while sparing VHL-intact normal and malignant cells, despite causing slightly weaker glycolytic suppression. Mechanistic investigations revealed that ENO2 ablation inactivated up to ~78% of VHL loss-induced oncogenic effectors, including a pleiotropic oncoprotein MDK, through dual modulation of lactate metabolism and interferon signaling. Collectively, this work reveals ENO2 as a genotype-specific metabolic dependency in ccRCC, thereby enabling precision glycolytic therapy. Our work also suggests that targeting physiologically redundant metabolic isoenzymes may offer a precision medicine strategy for cancers with defined genetic alterations.</p>","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":" ","pages":""},"PeriodicalIF":12.2,"publicationDate":"2026-07-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13645809/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148444633","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Restoring the CD226 in CD8⁺T cells overcomes TIGIT-refractory immunity in HER2⁺ breast cancer.","authors":"Liyi Zhang, Jiaoduan Li, Bingqiu Xiu, Chen Zheng, Qi Zhang, Huixin Lu, Zehao Wang, Zhibo Shao, Jingyan Xue, Yayun Chi, Dongxi Xiang, Jiong Wu","doi":"10.1038/s41419-026-09004-5","DOIUrl":"10.1038/s41419-026-09004-5","url":null,"abstract":"<p><p>Immune checkpoint blockade (ICB) has shown limited activity in HER2⁺ breast cancer, yet the mechanisms underlying this refractoriness remain unclear. Integrating single-cell transcriptomics from untreated human and murine HER2⁺ tumors with an anti-HER2 non-sensitive mouse model, a neoadjuvant non-pCR patient cohort, functional co-culture assays, and in vivo perturbations, we identify TIGIT signaling from malignant cells (via CD112) to CD8⁺T cells as a dominant immunosuppressive axis. High TIGIT and CD112 expression correlate with poor clinical outcomes and with the enrichment of TIGIT⁺CD8⁺T cells after anti-HER2 therapy. Therapeutically, combining anti-TIGIT with anti-HER2 reprograms the tumor microenvironment, expanding activated CD8⁺ T cells with enhanced effector function, increasing IFN-γ production, and restoring MHC-I on tumor cells. A central mechanistic node is the reinstatement of the costimulatory receptor CD226 on CD8⁺T cells. TIGIT blockade induces CD226, and CD8 dependence is required for efficacy. Neutralizing CD226 abrogates cytotoxicity and IFN-γ secretion. Multiplex tissue analyses further show that intratumoral CD8⁺CD226⁺T-cell density predicts improved overall and disease-free survival in HER2⁺ disease. Collectively, these data reveal that restoring CD226-mediated co-stimulation overcomes TIGIT-refractory immunity and sensitizes HER2⁺ tumors to anti-HER2 therapy, positioning CD226 as both a pharmacodynamic driver and a clinically actionable biomarker for patient selection and response monitoring. Anti-HER2 therapy fails in HER2⁺ breast cancer due to immunosuppression. This study shows tumor engagement of TIGIT on CD8⁺ T cells suppresses anti-tumor function. Combining anti-TIGIT with anti-HER2 blocks this suppression, reinvigorating CD8⁺ T cells via CD226 and enabling tumor clearance. This combination strategy overcomes therapeutic resistance.</p>","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":" ","pages":""},"PeriodicalIF":12.2,"publicationDate":"2026-07-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13642357/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148435277","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Antisense oligonucleotides treatment uncovers differences in the modulation of dysregulated intracellular pathways in Spinal Muscular Atrophy motoneurons.","authors":"Maria P Miralles, Isabel Gimenez-Fernandez, Maria Beltran, Alba Sansa, Laura Martínez-España, Jordi Calderó, Manuel Portero-Otín, Rosa M Soler, Ana Garcera","doi":"10.1038/s41419-026-09105-1","DOIUrl":"10.1038/s41419-026-09105-1","url":null,"abstract":"<p><p>Spinal Muscular Atrophy (SMA) is a neuromuscular genetic disorder resulting from the mutation or deletion of the Survival Motor Neuron 1 (SMN1) gene and the reduction of the Survival Motor Neuron (SMN) protein. As a result, SMN level in SMA depends on the almost identical copy gene SMN2, which produces a small amount of functional SMN due to a silent mutation in exon 7. SMN deficiency critically impairs spinal cord motoneuron (MN) function, causing progressive degeneration. Advances in SMA therapeutics have significantly improved clinical management and prognosis. However, therapeutic outcomes vary among SMA patients, resulting in broad heterogeneity in phenotypes and clinical trajectories; consequently, more focused investigation on the underlying disease mechanisms is essential. One of the FDA-approved treatments is nusinersen, an antisense oligonucleotide (ASO) designed to enhance SMN2 exon 7 splicing and increase SMN protein. The present study used non-SMA and SMA MNs differentiated from human induced Pluripotent Stem Cells (hiPSCs) to analyze the effect of a nusinersen-like ASO treatment on intracellular pathways altered in SMA MNs. ASO treatment efficiently increased SMN, prevented MN degeneration, and decreased apoptotic markers in SMA MNs. Furthermore, treatment increased Gemin3 protein and the NF-κB members, IKKβ and RelA. Nevertheless, ASO did not revert alterations of the autophagy markers LC3-II and p62/SQSTM1, and the calpain activation product α-fodrin 145/150 kDa. Our observations indicate that nusinersen-like ASO treatment might be insufficient to counteract the full spectrum of intracellular alterations occurring in SMN-reduced MNs. Therefore, supplementary compounds targeting these unrecovered pathways might supply additional protective effects on degenerating MNs.</p>","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":" ","pages":""},"PeriodicalIF":12.2,"publicationDate":"2026-07-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13642960/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148435274","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Lineage-specific Nrf2 signaling orchestrates distinct neuroprotective mechanisms in acute ischemic stroke.","authors":"Xiaoxiao Li, Chenchen Xu, Wenxin Xia, Caiyu Yang, Xin Wang, Jianjian Dong, Yongsheng Han","doi":"10.1038/s41419-026-09047-8","DOIUrl":"10.1038/s41419-026-09047-8","url":null,"abstract":"<p><p>Nuclear factor erythroid 2-related factor 2 (Nrf2), a key antioxidant transcription factor, shows neuroprotective potential in ischemic stroke (IS); however, its cell type-specific functions across different neural lineages remain partially understood. This study innovatively employs a comparative knockout paradigm, utilizing neural lineage knockout (Nrf2^flox/flox; Nestin-Cre, targeting neural progenitor cells and their derived lineages) and astrocyte-biased knockout (Nrf2^flox/flox; GFAP-Cre) mouse models, combined with an in vitro co-culture system, to elucidate the lineage-dependent and differential protective mechanisms of Nrf2 in acute IS (AIS). Results demonstrated that both knockout models exacerbated neurological deficits, increased cerebral infarct volumes, and reduced cerebral blood flow. However, a marked phenotypic divergence was observed. The Nestin-Cre model exhibited more severe neurological deterioration, associated with dysregulated iron metabolism, enhanced lipid peroxidation, and aggravated neuroinflammation, suggesting a predominant role for neuronal Nrf2 in counteracting ferroptosis and neuroinflammatory responses. In contrast, the GFAP-Cre model did not induce ferroptosis but promoted neurotoxic A1-type astrocyte polarization and enhanced inflammatory injury via NF-κB pathway activation. This finding underscores the unique function of astrocytic Nrf2 in modulating the neuroinflammatory microenvironment. These cell-type-specific effects were further validated in an in vitro oxygen-glucose deprivation/reoxygenation (OGD/R) model. Through this cross-lineage comparative analysis, our study systematically elucidates, for the first time, the distinct protective mechanisms of Nrf2 in neurons and astrocytes, thereby advancing understanding of its functional heterogeneity and providing a novel theoretical basis for developing cell-type-biased, Nrf2-targeted therapeutic strategies.</p>","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":" ","pages":""},"PeriodicalIF":12.2,"publicationDate":"2026-07-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13645789/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148435231","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"MARCKS as a mediator and target for pathological tunneling nanotubes between patient-derived glioblastoma cells and astrocytes.","authors":"Lauren C Nassour-Caswell, Mayada Ahmed, Shane T Rich-New, Taylor L Schanel, Manoj Kumar, Nicholas J Eustace, Timothy D Rohrbach, John S Jarboe, Patricia H Hicks, Joshua C Anderson, Christopher D Willey","doi":"10.1038/s41419-026-09109-x","DOIUrl":"10.1038/s41419-026-09109-x","url":null,"abstract":"<p><p>During glioblastoma (GBM) progression, therapeutic resistance is influenced by a heterogeneous network of tumor- and tumor-promoting subpopulations within the tumor microenvironment. Therapeutic interventions against tumor cells, such as chemoradiotherapy, can further induce adaptive defense mechanisms mediated by sophisticated intercellular communication and aberrant signaling pathways. Tunneling nanotubes (TNTs) have emerged as key mediators of this process, promoting tumor cell survival through metabolic rescue while enabling the recruitment and reprogramming of surrounding normal cells into tumor-supportive phenotypes. This dynamic is exemplified in GBM, where TNT-mediated interactions between brain tumor-initiating cells (BTICs) and normal human astrocytes (NHAs) highlight the need to elucidate the molecular mediators underlying this crosstalk. Myristoylated Alanine Rich C-Kinase Substrate (MARCKS) has never been investigated as a potential regulator of TNTs despite several overlapping signaling pathways and its influence on GBM therapeutic resistance. In the present study, we demonstrate a role for the MARCKS effector domain (ED) and PKC activation in the formation and functionality of TNTs between PTEN-null GBM BTICs and NHAs. We employ a MARCKS phosphorylation site (MPS) peptide derived from MARCKS effector domain (MED2), PKC-targeting drugs, and an inducible MARCKS ED U87 model to elucidate a potential role for MARCKS phosphorylation and PKC in TNT regulation between GBM cells (i.e., BTICs or U87s) and NHAs.</p>","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":" ","pages":""},"PeriodicalIF":12.2,"publicationDate":"2026-07-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13642262/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148435286","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}