Cell Death Discovery最新文献

{"title":"Inhibition of RIPK1/RIPK3-MLKL inflammatory signaling pathway activation attenuates preterm birth.","authors":"Xuexiang Bing, Yongqing Wang, Jiacui Zheng, Guodong Gao, Jinxiao Jiang, Lanlan Liu, Xue Zhang","doi":"10.1038/s41420-026-03093-z","DOIUrl":"https://doi.org/10.1038/s41420-026-03093-z","url":null,"abstract":"<p><p>Preterm birth (PTB) is a principal contributor to neonatal morbidity, wherein inflammation and dysregulated cell death pathways are implicated as key drivers in its pathogenesis. However, the role of the RIPK1/RIPK3-MLKL signaling axis, a critical regulator of necroptosis and inflammatory responses, remains poorly characterized in the context of PTB. Here, we sought to elucidate the role of RIPK1-mediated activation of the RIPK3-MLKL pathway in placental inflammation and its involvement in PTB pathogenesis. In vitro experiments were conducted using TNF-α-stimulated HTR8/SVneo trophoblasts, while an LPS-induced murine model was employed to mimic inflammation-associated PTB. RIPK1 expression was modulated via shRNA-mediated knockdown or pharmacological inhibition with GSK2982772 and Nec-1. Molecular analyses included qPCR, Western blotting, ELISA, and the assessment of necroptosis via PI staining. We found that TNF-α and LPS significantly upregulated RIPK1 expression and activated the RIPK3-MLKL pathway in both the cellular and animal models. RIPK1 knockdown or pharmacological inhibition attenuated TNF-α-induced proinflammatory cytokine release (IL-1β, IL-6, TNF-α), uric acid accumulation, RIPK3-MLKL pathway activation, and necroptosis in trophoblasts at both 24 and 48 h. Notably, in vivo treatment with Nec-1 ameliorated LPS-induced placental damage. Collectively, our findings demonstrate that RIPK1 drives inflammation and necroptosis in PTB through RIPK3-MLKL activation, suggesting that targeting RIPK1 may represent a promising therapeutic strategy for inflammation-associated preterm labor.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":" ","pages":""},"PeriodicalIF":7.0,"publicationDate":"2026-04-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147716275","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":"Nicotinamide N-methyltransferase as a therapeutic target in taxane-resistant castration-resistant prostate cancer.","authors":"Buse Cevatemre, Ezgi Karyemez, Ipek Bulut, Hamzah Syed, Mehmet Gönen, Ahmet Tarik Baykal, Tugba Bagci-Onder, Ceyda Acilan","doi":"10.1038/s41420-026-03110-1","DOIUrl":"https://doi.org/10.1038/s41420-026-03110-1","url":null,"abstract":"<p><p>Drug resistance in patients remains a significant obstacle to successful treatment, even with improvements in cancer treatment strategies. Resistance to taxanes, such as docetaxel (Dtx) and cabazitaxel (Cbz), frequently emerges in castration resistant prostate cancer (CRPC). Through pulse selection of the parental cells (DU145), we established Dtx- and Cbz-resistant CRPC cell models and integrated different omic approaches, including transcriptomics and proteomics, to determine the molecular signatures underlying taxane resistance. Interestingly, several genes were regulated in the same direction (up- or down-regulation) at both the gene and protein expression levels in resistant cells compared to parental cells, suggesting that alterations primarily occur at the transcriptional level and manifest at the protein level. Among the differentially regulated genes, Cysteine Rich Protein 2 (CRIP2), a gene associated with tumor suppressor function, has been found to be the most downregulated in taxane-resistant cells. Conversely, Nicotinamide N-Methyltransferase (NNMT) exhibited a significant upregulation and has been validated in the context of taxane resistance. Its overexpression was shown to promote taxane resistance in two different CRPC cell lines, whereas depletion via siRNA or gRNA, as well as treatment with 1-methylnicotinamide (1-MNA, used as a feedback inhibitor)resensitized the resistant cells. RNA-sequencing of NNMT-knockout (CRISPR-Cas9) cells has indicated involvement of TGFβ signaling, and suppressing this pathway has further increased the taxane sensitivity. Epithelial Mesenchymal Transition (EMT) was another pathway depleted upon knockout, and subsequent analysis revealed a significant correlation between NNMT and EMT-related genes (VIM, CDH2, FN1, TGFB1, and ZEB2) in both the Cancer Cell Line Encyclopedia (CCLE) panel and patient data. Additionally, in cancers other than PC, NNMT has been observed to predict treatment outcomes, and notably, among the patients with a high EMT signature, elevated NNMT levels were associated with decreased overall survival. More importantly, NNMT-high patients were found to be non-responders to taxane-containing chemotherapy regimens. Collectively, our findings suggest that targeting NNMT and the pathways it affects, such as TGFβ, offers a viable approach for addressing taxane-resistant PC.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":" ","pages":""},"PeriodicalIF":7.0,"publicationDate":"2026-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147716398","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":"Mytho/Phaf1 is required to prevent DNA damage and tissue degeneration in Danio rerio.","authors":"Tommaso Pagliarusco, Anais Franco-Romero, Francesca Terrin, Filippo Citton, Ludovica Carducci, Nicola Facchinello, Camilla Maria Fontana, Marta Giacomazzo, Ranieri Verin, Maria Berica Rasotto, Lisa Locatello, Luisa Dalla Valle, Marco Sandri","doi":"10.1038/s41420-026-03106-x","DOIUrl":"https://doi.org/10.1038/s41420-026-03106-x","url":null,"abstract":"<p><p>mytho (Macroautophagy and YouTH Optimizer) is a novel FoxO-dependent gene that has been recently identified to control health- and life-span in Caenorhabditis elegans via autophagy regulation. However, the role of this gene in tissues development and function in vertebrates has not yet been established. To address these issues, we generated a zebrafish mytho KO model and observed that mutants exhibited a higher mortality rate than wild-type (WT) siblings during the first month of life and a lower resistance to oxidative stress. mytho silencing resulted in a decrease in larval locomotor activity and muscle birefringence and caused alteration of adult muscle structure. Autophagy impairment was confirmed in tissues with the highest mytho expression such as brain, muscle and testis. Finally, mutants showed tissue degeneration in pancreas, retina and muscle, morphological alterations in gonads of both sexes and a reduction of reproductive capabilities of males. Importantly, males presented a higher incidence of seminomas, a testicular cancer. The increased susceptibility to cancer is associated with an enhanced DNA fragmentation in sperm cells. In conclusion, this study highlights the key role of Mytho in maintaining proper tissue function and DNA integrity.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":" ","pages":""},"PeriodicalIF":7.0,"publicationDate":"2026-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147716288","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":"Lipid-anchored melanotransferrin mediates transferrin-independent iron uptake and ferritin storage in mammals.","authors":"Mei Mei Tian, Jacqueline W C Tiong, Reinhard Gabathuler, Garnet Martens, Elaine C Humphrey, Wilfred A Jefferies","doi":"10.1038/s41420-026-03043-9","DOIUrl":"https://doi.org/10.1038/s41420-026-03043-9","url":null,"abstract":"<p><p>Non-transferrin-bound iron (NTBI) transport constitutes a critical pathway for cellular iron uptake in the kingdom Animalia that remains mechanistically unresolved. Its physiological importance is underscored by atransferrinemia, a rare disorder in which individuals lacking plasma transferrin nonetheless retain the capacity to distribute dietary iron to essential organs, implying the presence of compensatory iron transport routes. Melanotransferrin (MFI2; also designated p97 or CD228) is an evolutionarily conserved iron-binding protein that exists in both a secreted form and a glycosylphosphatidylinositol (GPI)-anchored membrane-bound form, suggesting a fundamental role in iron homeostasis. In mammals, the secreted isoform mediates iron transport across the blood-brain barrier, whereas GPI-anchored MFI2 is expressed by microglia in proximity to β-amyloid plaques in Alzheimer's disease, implicating it in neuroinflammatory processes. Moreover, it is also recognized as a tumor-associated antigen in melanoma, indicating a potential role in tumor progression. In the present study, we delineate a previously uncharacterized NTBI internalization pathway mediated by GPI-MFI2. Using human melanoma cells, we demonstrate that GPI-MFI2, together with its bound iron, undergoes caveolae-dependent internalization followed by trafficking through a Rab5-mediated endosomal pathway. The internalized iron is subsequently trafficked to ferritin, underscoring its functional importance in maintaining intracellular iron stores. These findings establish the first molecularly defined pathway for transferrin-independent iron uptake in mammalian cells, providing a framework to interrogate MFI2's role in iron mobilization and dysregulation in neurodegeneration and cancer.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":" ","pages":""},"PeriodicalIF":7.0,"publicationDate":"2026-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147716317","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":"Uttroside B, a US FDA-designated 'Orphan Drug', mitigates the development of hepatocellular carcinoma and its pulmonary metastasis via EGFR/ERK-mediated inhibition of SREBP-1 and STAT-3.","authors":"Chenicheri Kizhakkeveettil Keerthana, Tennyson P Rayginia, Kalishwaralal Kalimuthu, Sandhini Saha, Nair H Haritha, Amrutha Nisthul Areekkara, Mundanattu Swetha, Sreekumar U Aiswarya, Lekshmi R Nath, Sanjay Suresh Varma, Arun Viswanathan, Jannet S, Shirly J, Aparna Js, Archana Praveen, Vishnu Sunil Jaikumar, Sankar Sundaram, Nikhil Ponnoor Anto, Tushar K Maiti, C Sadasivan, Noah Isakov, Ravi S Lankalapalli, Kuzhuvelil B Harikumar, Ruby John Anto","doi":"10.1038/s41420-026-03055-5","DOIUrl":"https://doi.org/10.1038/s41420-026-03055-5","url":null,"abstract":"<p><p>Hepatocellular carcinoma (HCC) is a highly aggressive tumor with rapid propensity for extrahepatic metastasis, which critically limits long-term clinical benefits of conventional chemotherapeutics and decreases the overall survival rate of patients. Our previous reports have documented the anti-HCC potential and pharmacological safety of uttroside B (Utt-B). Herein, we illustrate the role of EGFR/ERK signaling axis and their downstream targets SREBP-1 and STAT-3, in the action mechanism of Utt-B. Further, the current study also demonstrates the strong anti-invasive and anti-metastatic properties of Utt-B against liver cancer. Pharmacological inhibition of EGFR/ERK axis led to the abrogation of Utt-B-mediated cytotoxicity and induction of apoptosis, in vitro. siRNA-mediated silencing of EGFR resulted in the attenuation of the cytotoxic, pro-apoptotic and anti-invasive effects of Utt-B, in vitro, thereby validating the regulatory role of EGFR in orchestrating the anti-HCC and anti-metastatic potential of Utt-B. In vivo studies confirmed that treatment with Utt-B mitigates the development of primary hepatic tumors in an orthotopic xenograft model and impedes the pulmonary metastasis of HCC in a murine metastasis model, via the down-regulation of EGFR/ERK axis. Taken together, the current findings attest to the exceptional therapeutic potential of Utt-B against primary and metastatic HCC and highlight its potential as a candidate drug to be evaluated in the clinics for the benefit of HCC patients having limited prognosis and therapeutic options.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":" ","pages":""},"PeriodicalIF":7.0,"publicationDate":"2026-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147697674","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":"NAT10 promotes gallbladder cancer progression by remodeling cholesterol metabolism via PCSK9 mRNA acetylation.","authors":"Zheng-Yu Chen, Ming-Yang Wang, Ben Ma, Cheng Zhao, Li-Jia Pan, Zi-Ying Wang, Yu-Ting Wang, Pan-Yi Mao, Xiang Zhao, De-Long Qin, Yi-Jun Shu, Yun-Jiao Zhang, Shan-Shan Xiang, Ping Dong","doi":"10.1038/s41420-026-03104-z","DOIUrl":"https://doi.org/10.1038/s41420-026-03104-z","url":null,"abstract":"<p><p>Gallbladder cancer (GBC) is a highly aggressive biliary tract tumor with a poor prognosis, underscoring the critical need for new therapeutic strategies. N-acetyltransferase 10 (NAT10), the sole writer of N4-acetylcytidine (ac4C), is upregulated in multiple cancers and is implicated in tumor pathogenesis. We observed significant NAT10 overexpression in GBC. Functional studies confirmed that NAT10 drives growth, migration, and malignant progression of GBC cells. We mechanistically linked this to NAT10-mediated ac4C modification, which stabilizes proprotein convertase subtilisin/kexin type 9 (PCSK9) mRNA, thereby reprogramming cholesterol metabolism and triggering intracellular cholesterol accumulation. This cholesterol buildup subsequently activates the PI3K/AKT pathway, stimulating cancer cell proliferation, migration, and invasion. Therapeutically, targeting NAT10 with Remodelin potently suppressed GBC proliferation. Importantly, Remodelin synergized with the standard chemotherapeutic agent gemcitabine to markedly enhance its therapeutic effect. Thus, our study defines a novel mechanism in which NAT10-dependent ac4C modification stabilizes PCSK9 mRNA to promote cholesterol-driven malignancy, nominating NAT10 as a compelling therapeutic target in GBC.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":" ","pages":""},"PeriodicalIF":7.0,"publicationDate":"2026-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147697729","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":"Regulation of lipid droplets accumulation by the Hippo-YAP/COX2 signaling pathway in neomycin-induced ototoxicity.","authors":"Wenli Hao, Song Gao, Suhan Guo, Jingjing Luo, Siyu Li, Junze Lu, Lulu Jiang, Jie Lu, Nan Wang, Aijia Ran, Xiaoyun Qian, Xia Gao, Chenjie Yu, Cheng Cheng","doi":"10.1038/s41420-026-03115-w","DOIUrl":"https://doi.org/10.1038/s41420-026-03115-w","url":null,"abstract":"<p><p>Lipid metabolism is an important biological process that maintains the dynamic balance of several key functions, such as intracellular energy metabolism, signal transduction, and membrane remodeling. However, the role of lipid metabolism in auditory function and the underlying mechanisms remain unclear. Our results reveal that the neomycin exposure disrupts lipid metabolism in auditory system. We find that neomycin-induced hair cells (HC) damage leads to abnormal lipid droplets (LD) accumulation. Further research reveals that decreased YAP expression is a key factor that contributes to abnormal LD accumulation. In both in vivo and in vitro studies, Yap overexpression reduces abnormal LD accumulation and mitigated HC damage. To further investigate its downstream mechanisms, we perform a cross-analysis of Yap-related and lipid metabolism-related genes, identifying that Cox2 is a key downstream target of Yap that contributes to LD accumulation and HC damage. Our work provides clear evidence for the role of lipid metabolism in neomycin-induced hearing loss and elucidates underlying mechanism of Yap/Cox2 pathway. These findings provide new perspectives and avenues for the clinical treatment of sensorineural hearing loss.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":" ","pages":""},"PeriodicalIF":7.0,"publicationDate":"2026-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147697671","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":"Ubiquitin ligase RCHY1 regulates autophagosome-lysosome fusion.","authors":"Ruchi Umargamwala, Jantina Manning, Julian M Carosi, Donna Denton, Sharad Kumar","doi":"10.1038/s41420-026-03088-w","DOIUrl":"https://doi.org/10.1038/s41420-026-03088-w","url":null,"abstract":"<p><p>Autophagy is a fundamental cellular recycling process that maintains homeostasis during animal development and under nutrient-limiting conditions. In our previous work, we employed autophagy-dependent cell death (ADCD) in the obsolete Drosophila larval midgut as a model to identify the enzymes involved in protein modification via ubiquitination with potential roles in autophagy regulation. From a genetic screen we identified RING E3 ligase RCHY1 as a candidate regulator. Here, we demonstrate that RCHY1 is essential for autophagy regulation during larval midgut ADCD in Drosophila and promotes autophagic flux in HeLa cells. Loss of Rchy1 impaired autophagosome-lysosome fusion and led to the accumulation of amphisomes in larval midgut cells. Similarly, depletion of RCHY1 in HeLa cells disrupted autophagic flux and reduced autolysosome formation, indicating evolutionary conservation of its function. Collectively, our findings identify RCHY1 as a putative regulator of autophagy that facilitates autophagosome-lysosome fusion.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":" ","pages":""},"PeriodicalIF":7.0,"publicationDate":"2026-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147688357","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":"Dysregulated nuclear Lamin B1 in DYT1 dystonia thickens nuclear lamina and disrupts 14-3-3 proteins.","authors":"Yuntian Duan, Masood Sepehrimanesh, Md Abir Hosain, Haochen Cui, Jacob Stagray, Xinggui Shen, Ying Xiao, Yuqing Li, Chun-Li Zhang, Baojin Ding","doi":"10.1038/s41420-026-03090-2","DOIUrl":"10.1038/s41420-026-03090-2","url":null,"abstract":"<p><p>Childhood-onset DYT1 dystonia is a severe movement disorder caused by a heterozygous ΔE mutation in TOR1A, yet the molecular mechanisms driving disease remain unclear. The nuclear lamina, a key structural scaffold for nuclear integrity and gene regulation, has emerged as a potential site of dysfunction. Here, we investigated the role of nuclear Lamin B1 dysregulation in DYT1 pathology using patient fibroblasts and human iPSC-derived neurons. We show that excess Lamin B1 thickens the nuclear lamina, distorts nuclear architecture, and impairs nucleocytoplasmic transport. Proteomic profiling further revealed that dysregulated Lamin B1 disrupts neuronal signaling pathways, with 14-3-3 proteins, highly abundant chaperones essential for neuronal development and homeostasis, being the most affected. Functional studies demonstrated that loss of 14-3-3 proteins compromises neuron differentiation, whereas restoring their levels rescues DYT1 neuronal defects by correcting Lamin B1 mislocalization. These findings establish a mechanistic link between nuclear architecture, intracellular signaling, and neuronal deficits in DYT1 dystonia, and identify Lamin B1 and 14-3-3 proteins as promising therapeutic targets with broader relevance to neurological disease.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":" ","pages":""},"PeriodicalIF":7.0,"publicationDate":"2026-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147688350","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":"Dual inhibition of xCT and GGCT induces ferroptosis in glioblastoma cells by depleting cysteine and disrupting redox homeostasis.","authors":"Masaya Mori, Hiromi Ii, Mai Matsumura, Yuhi Sone, Haruna Kumamoto, Kana Sakurai, Teruna Fujino, Nanami Nihei, Nana Hongo, Kozue Nose, Takahiro Matsumoto, Mitsugu Fujita, Susumu Nakata","doi":"10.1038/s41420-026-03108-9","DOIUrl":"https://doi.org/10.1038/s41420-026-03108-9","url":null,"abstract":"<p><p>Glioblastoma is the most aggressive and treatment-resistant brain tumor. Ferroptosis, an iron-dependent form of regulated cell death caused by lipid peroxidation, has emerged as a promising therapeutic strategy; however, intrinsic resistance to ferroptosis limits its therapeutic efficacy. Here, we demonstrate that metabolic depletion of cysteine through dual inhibition of exogenous and endogenous sources represents a novel approach to overcome this resistance. While inhibition of xCT suppresses cystine uptake and induces ferroptosis, we identified γ-glutamylcyclotransferase (GGCT), a key enzyme in glutathione (GSH) degradation, as a metabolic compensation pathway that regenerates cysteine to sustain redox homeostasis. Blocking both xCT and GGCT synergistically depleted intracellular cysteine and GSH, leading to excessive accumulation of reactive oxygen species (ROS), lipid peroxidation, and ferroptotic cell death in glioblastoma cells. Importantly, dual inhibition markedly suppressed tumor growth in vivo and enhanced oxidative stress in tumor tissues, as evidenced by 4-hydroxynonenal accumulation. These findings uncover a previously unrecognized mechanism by which GGCT confers ferroptosis resistance by maintaining intracellular redox balance. Targeting the xCT-GGCT axis effectively disrupts redox homeostasis and eliminates metabolic plasticity that underlies ferroptosis resistance in glioblastoma. This study provides a mechanistic and translational rationale for developing dual inhibition of xCT and GGCT as a promising therapeutic strategy against this lethal and therapy-refractory cancer.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":" ","pages":""},"PeriodicalIF":7.0,"publicationDate":"2026-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147688043","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}