Cell Death Discovery最新文献

{"title":"Correction: RNA binding motif protein RBM41 promotes colorectal tumorigenesis by impeding the maturation of NDRG1 pre-mRNA.","authors":"Yanxin Liu, Jianfeng Mu, Jiming Yu, Qirong Li, Tiantian Li, Qiang Feng, Tong Sun, Ke Sun, Yang Hao, Jinhai Yu, Dongxu Wang","doi":"10.1038/s41420-026-03341-2","DOIUrl":"10.1038/s41420-026-03341-2","url":null,"abstract":"","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":"12 1","pages":""},"PeriodicalIF":10.4,"publicationDate":"2026-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13661604/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149179695","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":"p53 wild-type/low c-Myc-expressing ONS76 pediatric medulloblastoma cells become senescent after gamma-irradiation and can be eliminated by senolytic substances.","authors":"Jessica Sonntag, Ronja-Linda Preugschas, Danny Jazmati, Nan Qin, Judith Neuwahl, Christiane Matuschek, Marc Remke, Wilfried Budach, Juliane Hörner-Rieber, Dennis Sohn","doi":"10.1038/s41420-026-03404-4","DOIUrl":"10.1038/s41420-026-03404-4","url":null,"abstract":"<p><p>Craniospinal irradiation (CSI) is an indispensable part of oncological treatment for pediatric medulloblastoma. However, despite significantly improving oncological outcome, it is also associated with severe short- and long-term side effects such as inflammation and impaired neurocognition. The presence of senescent cells has been identified as a potential contributing factor to these issues. In our study, we demonstrate that p53 wild-type and c-Myc-low-expressing ONS76 medulloblastoma cells underwent senescence, a terminal and stable cell cycle arrest, after exposure to gamma irradiation (γIR). In contrast, p53-mutated UW228-3 cells exhibited apoptosis following the same treatment. ONS76 cells displayed typical senescence properties, including cell and nuclei enlargement, an active DNA damage response with stabilization of p53 and increased expression of its target gene, the CDK inhibitor p21^WAF1/CIP1, as well as elevated senescence-associated beta-galactosidase activity and lipofuscin accumulation. Knockdown of p53 or p21 expression with siRNAs abolished γIR-mediated senescence. Furthermore, overexpression of c-Myc resulted in a partial shift from senescence to cell death induction after γIR treatment, which was inhibited by using the caspase-inhibitor q-VD-OPh. The γIR-exposed ONS76 cells showed susceptibility to senolytic substances, such as the BCL-2 family inhibitor Navitoclax and the PI3K-inhibitors PX-866 and BAY80-6946, which specifically target senescent cells. In conclusion, employing senolytics on irradiated medulloblastoma cells with wild-type p53 and low c-Myc expression may lead to reduced therapeutic side effects as well as attenuate tumor relapse and potentially minimize CSI doses required for effective tumor cell elimination.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":"12 1","pages":""},"PeriodicalIF":10.4,"publicationDate":"2026-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13649648/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149135215","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":"Targeting common denominators of DNA damage tolerance mechanisms as therapeutic strategy to cope with dynamic phenotypic changes in triple-negative breast cancer cells.","authors":"Kathrin Niedermayer, Sara Greco, Anke Oechsle, Tanja Köhler, Klaus Pantel, Thomas W P Friedl, Wolfgang Janni, Brigitte Rack, Kerstin Pfister, Vanesa Gottifredi, Lisa Wiesmüller","doi":"10.1038/s41420-026-03377-4","DOIUrl":"10.1038/s41420-026-03377-4","url":null,"abstract":"<p><p>Triple negative breast cancer (TNBC) is the most aggressive type of breast cancer with limited treatment options and a propensity towards chemoresistance. Given the lack of targetable receptors, treatment relies primarily on chemotherapy. While mechanisms leading to chemoresistance are vastly unknown, DNA damage tolerance (DDT) pathways have emerged as potential drivers of chemoresistance. Herein, we report a phenotypic characterization of four TNBC- and six non-TNBC cell lines, which supports the relevance of DDT in the TNBC response to chemotherapy. We unveiled an association between DDT pathway activation through PCNA-ubiquitination, augmented epithelial-to-mesenchymal transition (EMT) and stemness features, specifically in 3D spheroid culture from TNBC cells. Analysis of replication dynamics revealed a pronounced replication slowdown in 3D- versus 2D-cultured TNBC but not in non-TNBC cells. The exploration of DDT pathway usage in three TNBC cell lines (MDA-MB-231, Hs578t, MDA-MB-468) uncovers reliance on ZRANB3-, HLTF- and SMARCAL1-dependent fork reversal in 3D, while translesion DNA synthesis (TLS) polymerases (POLs) were more active under 2D conditions. Screening cytotoxicity with a panel of ten drugs targeting key DDT pathway components identified POLζ inhibition (JH-RE-06; IC₅₀ ≤ 7 µM/48 h) and CHK1 inhibition (PF477736; IC₅₀ ≤ 20 µM/48 h) as the most potent single-agent treatments in all three cell lines under both conditions. Mechanistically, both POLζ and CHK1 inhibition target several DDT pathways, in sum, causing replication slowdown, revealed consistently for CHK1. While TNBC cell lines were largely unresponsive to Olaparib mono-treatment, especially in 3D culture, all three cell lines were resensitized by combining Olaparib with low-dose POLζ-, CHK1-, or RAD51 inhibitor, except for 3D-cultured MDA-MB-231 cells, which may resist Olaparib due to their high ZRANB3 complex formation in the nucleus. These findings identify key DDT pathway components such as POLζ and CHK1 as druggable targets that alone or in combination with Olaparib may overcome chemoresistance in TNBC.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":"12 1","pages":""},"PeriodicalIF":10.4,"publicationDate":"2026-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13642338/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149104582","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":"JP-1302 inhibits RNA polymerase I transcription and induces nucleolar stress in cancer cell lines.","authors":"Sheetanshu Saproo, Styliani Papadaki, Johana Fernandez-Martinez, Pinky Sultana, Dimitris C Kanellis, Jiri Bartek, Mikael S Lindström","doi":"10.1038/s41420-026-03381-8","DOIUrl":"https://doi.org/10.1038/s41420-026-03381-8","url":null,"abstract":"<p><p>Cancer cells upregulate ribosomal RNA (rRNA) synthesis to sustain the elevated ribosome production that fuels rapid proliferation, creating a dependency that renders RNA polymerase I (Pol I) transcription a pharmacological vulnerability. JP-1302 is a blood-brain barrier-penetrant 9-anilinoacridine derivative developed as an α_2C-adrenergic receptor antagonist, but also recently identified as an RNA Pol II inhibitor at micromolar concentrations (~5-10 μM). Here we show that JP-1302 also suppresses Pol I-driven 47S pre-rRNA synthesis at submicromolar-to-low-micromolar concentrations, evidenced by loss of nascent EU-labelled rRNA and reduced activity of an rDNA promoter-driven luciferase reporter. This was accompanied by preferential proteasome-dependent degradation of the Pol I catalytic subunit POLR1A, independent of α_2C-adrenergic receptor signalling, displacement of POLR1A from the rDNA promoter and progressive disruption of nucleolar morphology. Growth inhibitory IC₅₀ values across a panel of normal and cancer cell lines, including glioblastoma, ranged from submicromolar to low micromolar. Nucleolar stress stabilised p53 and induced p21 expression at low-to-intermediate concentrations, without evidence of DNA damage at these doses (no γH2AX increase at concentrations sufficient to abrogate Pol I transcription). Interestingly, p53-null and p53-wild type cells showed comparable S-phase depletion in response to JP-1302. At higher concentrations, JP-1302 additionally caused covalent trapping of TOP2A/TOP2B, accompanied by delayed γH2AX induction, and enrichment of the FACT subunits SSRP1 and SPT16 on chromatin. Together, these findings identify JP-1302 as a pharmacologically distinct inhibitor of ribosome biogenesis with broader, dose-dependent chromatin-disruptive activity.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":"12 1","pages":""},"PeriodicalIF":10.4,"publicationDate":"2026-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13627690/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149104552","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":"Immunogenic cell death as a mechanism of synergy between sunitinib and ¹⁷⁷Lu-DOTATATE peptide receptor radionuclide therapy in pancreatic neuroendocrine tumors.","authors":"Markus Essler, Nadine Veit, Aurelia Müller, Milka Marinova, Barbara Kreppel","doi":"10.1038/s41420-026-03344-z","DOIUrl":"10.1038/s41420-026-03344-z","url":null,"abstract":"<p><p>Peptide receptor radionuclide therapy (PRRT) with ¹⁷⁷Lu-DOTATATE improves outcomes in neuroendocrine tumors (NETs), yet durable disease control remains limited in progressive pancreatic NET (pNET) and higher-grade disease. Combinations that enhance PRRT efficacy may be advantageous. As sunitinib has radiosensitizing and immunomodulatory effects, we explored the clinical activity and mechanistic basis of combining sunitinib with PRRT. Combination treatment with ¹⁷⁷Lu-DOTATATE (1-3 cycles; 7.4 GBq per cycle) and sunitinib at 37.5 mg/day was well tolerated and effective in a pilot group of heavily pretreated pNET patients with progressive disease. Treatment response was assessed by ⁶⁸Ga-DOTATOC PET/CT and serum tumor markers (CgA, NSE). Mechanistic studies were performed in QGP-1 pNET cells using proliferation and apoptosis assays, cell-cycle analysis, and immunogenic cell death (ICD) markers. Combination therapy was well tolerated and induced marked responses: three patients achieved near-complete responses and two partial responses on post-therapy ⁶⁸Ga-DOTATOC PET/CT. In vitro, ¹⁷⁷Lu-DOTATATE and sunitinib showed bidirectional sensitization: low-dose sunitinib reduced the LD50 of ¹⁷⁷Lu-DOTATATE, and low-activity ¹⁷⁷Lu-DOTATATE reduced the LD50 of sunitinib. ¹⁷⁷Lu-DOTATATE induced dose-dependent PARP cleavage and S/G2-M arrest; however, sunitinib shifted cell death toward late apoptosis/necrosis. The combination produced a more-than-additive increase in calreticulin exposure on the tumor cell surface and enhanced HMGB1 but not interleukin- 1ß- or interleukin-18-release compared with either monotherapy, indicating immunogenic late apoptosis/necrosis, without canonical inflammasome activation. Intermittent sunitinib combined with ¹⁷⁷Lu-DOTATATE PRRT demonstrated encouraging activity in progressive pNET. The mechanism of synergy in vitro was enhanced ICD, suggesting that immune responses contribute to the synergy in vivo.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":"12 1","pages":""},"PeriodicalIF":10.4,"publicationDate":"2026-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13588797/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149001382","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":"Anthracycline and antimetabolite, trigger distinct resistance mechanisms in TP53^mut AML.","authors":"Sanjeev Raghuwanshi, Andrei L Gartel","doi":"10.1038/s41420-026-03352-z","DOIUrl":"10.1038/s41420-026-03352-z","url":null,"abstract":"","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":"12 1","pages":""},"PeriodicalIF":10.4,"publicationDate":"2026-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13586370/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148987898","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":"Immunoregulatory role of quercetin in lung cancer.","authors":"Christine Carvalho, Elvedina Nendel, Susanne Mittler, Sonja Trump, Adriana Geiger, Jonas Willar, Mircea T Chiriac, Stefan Wirtz, Carol I Geppert, Susetta Finotto","doi":"10.1038/s41420-026-03312-7","DOIUrl":"10.1038/s41420-026-03312-7","url":null,"abstract":"<p><p>Long-term nourishment with quercetin, a naturally occurring plant flavonoid abundant in citrus fruits, buckwheat, and onions, has been associated with reduced risks of chronic diseases, including cancer. In this study, we evaluated the therapeutic potential and the anti-cancer properties of quercetin in lung cancer using in vitro, in vivo, and ex vivo models. Quercetin induced tumor cell cycle arrest via the p53-p21 axis and suppressed tumor cell migration in both the A549 and H520 human lung cancer cell lines. Moreover, it reduced oxidative stress and downregulated the protein expression of oncogenic markers such as EGFR and PD-L1 on the surface of A549 cells in a dose-response manner. Quercetin significantly attenuated the proliferation and migration of the tumor cells. In an in vivo model, quercetin decreased the tumor load without affecting the body weight. In the ex vivo model, quercetin treatment resulted in the induction of interferon alpha-2 (IFN-α2), a well-known anti-tumor cytokine. These findings demonstrate that quercetin exerts potent anti-tumoral and anti- inflammatory effects in lung cancer by regulating cell cycle, oxidative stress, and immune pathways. Overview of quercetin-induced cellular modulation in lung cancer [Created in BioRender] Quercetin had a direct effect on the tumor cell cycle, where it upregulated CDKN1A and downregulated CDK1 in both murine models and human lung cancer cell lines. Quercetin regulated the p53-p21 axis, decreased EGFR, PD-L1, and Ki67 expression, and also showed a strong inhibitory effect on tumor cell migration. It also conditioned the gut microbiome, promoting an increased abundance of SCFA-producing bacteria. At the same time, it led to an increase in IFN-α2 cytokine production. Quercetin also reprogrammed the splenic CD8 + T cell transcriptome, most notably by upregulating the tumor suppressor gene Ltf while also downregulating several oncogenes involved in proliferation and metastasis, namely POU6F1, Celsr1, ST3GAL6, Sik2, Adnp, and Jun.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":"12 1","pages":""},"PeriodicalIF":10.4,"publicationDate":"2026-09-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13574831/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148966656","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":"Reorientation of the SUMOylation landscape and altered L3mbtl2-mediated transcriptional activity in cancer-associated muscle contractile dysfunction.","authors":"Luis Vincens Gand, Mugeng Li, Katharina Brandt, Baoyu Zhou, Amel Nassar-Grioua, Julien Gondin, Edgar Becker, Andreas Pich, Theresia Kraft, Mamta Amrute-Nayak, Arnab Nayak","doi":"10.1038/s41420-026-03337-y","DOIUrl":"10.1038/s41420-026-03337-y","url":null,"abstract":"<p><p>Cachexia is a debilitating muscle-wasting disorder associated with a high mortality rate in cancer patients. However, the molecular mechanisms of muscle contractile dysfunction underlying cancer-induced cachexia (CIC) remain poorly characterized. Here, we demonstrated that CIC reorients global SUMOylation in skeletal muscle cells and alters the stability of various SUMO machinery components, particularly SUMO isopeptidases. The non-canonical polycomb repressor protein L3mbtl2 was among the predominant proteins with enhanced SUMOylation level in CIC. Surprisingly, in contrast to previous notions, we found that L3mbtl2 activates transcription of a large cohort of genes regulating muscle contraction. Mechanistically, L3mbtl2 associates with Ash2L, a component of the SET1/MLL histone methyltransferase complex. Increased SUMO modification of L3mbtl2 in CIC leads to partitioning of Ash2L from its target genes, resulting in impaired calcium handling, sarcomere disorganization and impeded muscle cell contractile properties. Our findings reveal an unprecedented connection between SUMO and CIC, a paradoxical SUMO-associated transcriptional activator function of L3MBTL2 and hold potential for developing therapeutic interventions to ameliorate CIC.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":"12 1","pages":""},"PeriodicalIF":10.4,"publicationDate":"2026-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13558696/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148918338","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":"The insulin-like growth factor 2 mRNA-binding protein 2 affects tumor cell metabolism via mitochondrial transporter activity and lipid alterations.","authors":"Sandra Kendzia, Susanne Franke, Marcello Pirritano, Eva Grafahrend-Belau, Nikolai Köhler, Theresa Bauchspiess, Sören Franzenburg, Marcus Höring, Elia Raab, Linus Schmeier, Sinem Sürmeli, Frank Erdmann, Johannes Klose, Jörg Kleeff, Michael Boettcher, Gerhard Liebisch, Josch K Pauling, Martin Simon, Björn H Junker, Sonja M Kessler","doi":"10.1038/s41420-026-03315-4","DOIUrl":"10.1038/s41420-026-03315-4","url":null,"abstract":"<p><p>The insulin-like growth factor 2 mRNA-binding protein (IGF2BP) family is overexpressed in cancer and associated with poor prognosis. IGF2BP2 has been linked to single metabolic alterations by acting on its RNA targets. Here, we used a comprehensive approach to elucidate the effects of IGF2BP2 on primary and lipid metabolism. ¹³C-metabolic flux analysis (MFA) combined with RNA-Seq data revealed that IGF2BP2 affects mitochondrial fluxes by regulating the expression of several mitochondrial transporters, such as mitochondrial pyruvate carrier 1 (MPC1) and uncoupling protein 2 (UCP2). Methyl pyruvate reversed the gene expression patterns of UCP2 and CPT1A in HCT116 IGF2BP2 knockout (KO) cells by bypassing MPC1. Interestingly, an altered expression of the transporter UCP2 was also observed in a patient-derived tumor organoid (PDO), in which IGF2BP2 was knocked down. The altered glutamine metabolism seen in the ¹³C-MFA and the citrate label data derived from extracted mitochondria confirm a rerouting of glutamine almost exclusively into the mitochondria and a reduction of glycolytic carbon intake into the mitochondria. Due to changes in palmitate labeling patterns, lipid stainings were performed, suggesting lipid accumulation in KO cells. A lipidomic analysis revealed altered compositions across almost all lipid species. Further, lipogenic genes involved in fatty acid and cholesterol metabolism were differentially expressed. Most of the differentially expressed genes are potential direct targets of IGF2BP2 based on publicly available IGF2BP2 CLIP data. Overall, these results show the influence of IGF2BP2 on the central carbon metabolism of cancer cells, primarily through its effects on MPC1 and the resulting effects on UCP2. The complex interaction of IGF2BP2 with the metabolic network provides important insights into tumor metabolism, particularly relevant to tumor growth and resistance to therapy.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":"12 1","pages":""},"PeriodicalIF":10.4,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13534510/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148873066","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":"Glutamine synthesis pathway promotes the survival and recurrence of dormant tumor cells in prostate cancer.","authors":"Bing Zhao, Qingwei Meng, Jun Zhou, Kun He, Hekang Ding, Jing Wang, Hailiang Hu, Lingfan Xu","doi":"10.1038/s41420-026-03282-w","DOIUrl":"https://doi.org/10.1038/s41420-026-03282-w","url":null,"abstract":"<p><p>Cancer cell dormancy presents a major obstacle to curative therapy, particularly in metastatic prostate cancer. Although the initial efficacy of hormonal therapy is satisfying, tumors will inevitably develop resistance. Dormant tumor cells may act as the initial source for the tumor recurrence, but the underlying mechanism remains largely unknown. Here we report that the glutamine synthesis pathway is required for cellular dormancy under androgen-deprived conditions. The key enzyme, glutamine synthetase (encoded by glutamate-ammonia ligase, GLUL), is upregulated during hormonal therapy, which leads to overabundant glutamine as a nutrient and an energy storage for tumor recurrence. The negative modulation of androgen receptor (AR) on GLUL enables activation of glutamine anabolism when AR is inhibited. Pharmacologically inhibiting GS's activity along with hormonal therapy results in cell apoptosis instead of dormancy, which significantly delays the progression of tumors into advanced PCa. In summary, we provide a novel perspective of how hormonal therapy eventually fails and highlight a combination treatment strategy to overcome therapeutic resistance of current hormonal therapy.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":"12 1","pages":""},"PeriodicalIF":10.4,"publicationDate":"2026-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149227422","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}