Cell Death Discovery最新文献

{"title":"Cardiomyocyte-restricted MIAT deletion is sufficient to protect against murine myocardial infarction.","authors":"Taiki Hayasaka, Satoshi Kawaguchi, Marisa N Sepúlveda, Jian-Peng Teoh, Bruno Moukette, Tatsuya Aonuma, Meena S Madhur, Ankit A Desai, Suthat Liangpunsakul, Simon J Conway, Il-Man Kim","doi":"10.1038/s41420-025-02352-9","DOIUrl":"10.1038/s41420-025-02352-9","url":null,"abstract":"<p><p>Myocardial infarction-associated transcript (MIAT), an intergenic long noncoding RNA (lncRNA), is conserved between rodents and humans and is directly linked to maladaptive cardiac remodeling in both patients and mouse models with various forms of heart failure (HF). We previously reported attenuation of cardiac stress, apoptosis, and fibrosis in a murine model of myocardial infarction (MI) with global MIAT ablation. Our transcriptomic profiling and mechanistic studies further revealed MIAT-induced activation of maladaptive genes, such as Hoxa4, Fmo2, Lrrn4, Marveld3, and Fat4. However, the source of MIAT and its contribution to MI and HF remain unknown. In this study, we generate a novel cardiomyocyte (CM)-specific MIAT conditional knockout mouse model, which exhibits improved cardiac function after MI. We further report that CM-specific MIAT ablation is sufficient to reduce cardiac damage, apoptosis, and fibrosis following chronic MI. Mechanistically, CM-specific MIAT deletion in mice leads to decreased expression of proapoptotic and pathological profibrotic genes, such as p53, Bak1, Col3a1, Col6a1, Postn, and Snail1 after chronic MI. These results enable us to begin to dissect cell-specific contributions to MIAT signaling and bolster the idea that MIAT plays a direct pathological role in CMs after MI.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":"11 1","pages":"70"},"PeriodicalIF":6.1,"publicationDate":"2025-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11842840/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143467239","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":"Lactylation in cancer: metabolic mechanism and therapeutic strategies.","authors":"Ying Sui, Ziyang Shen, Zhenling Wang, Jifeng Feng, Guoren Zhou","doi":"10.1038/s41420-025-02349-4","DOIUrl":"10.1038/s41420-025-02349-4","url":null,"abstract":"<p><p>Recent progress in cancer metabolism research has identified lactylation as a critical post-translational modification influencing tumor development and progression. The process relies on lactate accumulation and the activation of lactate-sensitive acyltransferases. Beyond its role in epigenetic regulation, lactylation has emerged as a significant factor in tumor metabolism and evolution, offering fresh opportunities for developing targeted therapies that transcend traditional approaches. This review explores the growing importance of lactylation in cancer biology and highlights its potential for advancing diagnostic tools and therapeutic strategies.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":"11 1","pages":"68"},"PeriodicalIF":6.1,"publicationDate":"2025-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11842571/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143467243","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":"Comparative microRNA signatures based on liquid biopsy to identify lymph node metastasis in T1 colorectal cancer patients undergoing upfront surgery or endoscopic resection.","authors":"Kazuaki Okamoto, Hiroaki Nozawa, Tsuyoshi Ozawa, Yoko Yamamoto, Yuichiro Yokoyama, Shigenobu Emoto, Koji Murono, Kazuhito Sasaki, Mitsuhiro Fujishiro, Soichiro Ishihara","doi":"10.1038/s41420-025-02348-5","DOIUrl":"10.1038/s41420-025-02348-5","url":null,"abstract":"<p><p>After endoscopic resection of T1 colorectal cancer (CRC) with a high risk of lymph node metastasis (LNM), additional surgery is required. However, the actual frequency of LNM based on conventional risk factors is less than 16%. There is a need for biomarkers to identify T1 CRC carrying a high risk of metastasis to avoid unnecessary radical surgery. Based on the comparison of serum miRNA between stage I/II and stage III from a large-scale in silico dataset, we conducted a validation analysis of the selected miRNAs using plasma samples from LNM-positive and LNM-negative T1 CRC patients who underwent endoscopic treatment followed by radical surgery at our hospital. In the validation cohort, the three-miRNA classifiers (miR-195-5p, miR-221-3p, and miR-193b-3p) effectively identified LNM-positive T1 CRC patients who received upfront surgery with an area under the curve (AUC) value of 0.74. Moreover, in T1 CRC patients after endoscopic resection, miR-195-5p and miR-221-3p were able to predict LNM with an AUC of 0.74. Plasma miRNA signatures may serve as effective predictors for LNM in T1 CRC both before upfront surgery and after endoscopic resection.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":"11 1","pages":"67"},"PeriodicalIF":6.1,"publicationDate":"2025-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11840149/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143456663","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":"A new understanding of Acanthamoeba castellanii: dispelling the role of bacterial pore-forming toxins in cyst formation and amoebicidal actions.","authors":"Abdelbasset Yabrag, Naeem Ullah, Palwasha Baryalai, Irfan Ahmad, Nikola Zlatkov, Eric Toh, Toril Lindbäck, Bernt Eric Uhlin, Sun Nyunt Wai, Aftab Nadeem","doi":"10.1038/s41420-025-02345-8","DOIUrl":"10.1038/s41420-025-02345-8","url":null,"abstract":"<p><p>Pore-forming toxins (PFTs) are recognized as major virulence factors produced by both Gram-positive and Gram-negative bacteria. While the effects of PFTs have been extensively investigated using mammalian cells as a model system, their interactions with the environmental host, Acanthamoeba castellanii remains less understood. This study employed high-throughput image screening (HTI), advanced microscopy, western blot analysis, and cytotoxicity assays to evaluate the impact of PFT-producing bacterial species on their virulence against A. castellanii. Our unbiased HTI data analysis reveals that the cyst induction of A. castellanii in response to various bacterial species does not correlate with the presence of PFT-producing bacteria. Moreover, A. castellanii demonstrates resistance to PFT-mediated cytotoxicity, in contrast to mammalian macrophages. Notably, Vibrio anguillarum and Ralstonia eutropha triggered a high frequency of cyst formation and cytotoxicity in infected A. castellanii. In summary, our findings reveal that A. castellanii exhibits a unique resistance to PFTs, unlike mammalian cells, suggesting its potential ecological role as a reservoir for diverse pathogenic species and its influence on their persistence and proliferation in the environment.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":"11 1","pages":"66"},"PeriodicalIF":6.1,"publicationDate":"2025-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11839945/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143456714","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":"Long-term adaptation of lymphoma cell lines to hypoxia is mediated by diverse molecular mechanisms that are targetable with specific inhibitors.","authors":"Lenka Daumova, Dmitry Manakov, Jiri Petrak, Dana Sovilj, Matej Behounek, Ladislav Andera, Ondrej Vit, Olga Souckova, Ondrej Havranek, Alex Dolnikova, Nicol Renesova, Liliana Tuskova, Lucie Winkowska, Nardjas Bettazova, Kristyna Kupcova, Marie Hubalek Kalbacova, Miriama Sikorova, Marek Trneny, Pavel Klener","doi":"10.1038/s41420-025-02341-y","DOIUrl":"10.1038/s41420-025-02341-y","url":null,"abstract":"<p><p>A large body of evidence suggests that hypoxia drives aggressive molecular features of malignant cells irrespective of cancer type. Non-Hodgkin lymphomas (NHL) are the most common hematologic malignancies characterized by frequent involvement of diverse hypoxic microenvironments. We studied the impact of long-term deep hypoxia (1% O2) on the biology of lymphoma cells. Only 2 out of 6 tested cell lines (Ramos, and HBL2) survived ≥ 4 weeks under hypoxia. The hypoxia-adapted (HA)b Ramos and HBL2 cells had a decreased proliferation rate accompanied by significant suppression of both oxidative phosphorylation and glycolytic pathways. Transcriptome and proteome analyses revealed marked downregulation of genes and proteins of the mitochondrial respiration complexes I and IV, and mitochondrial ribosomal proteins. Despite the observed suppression of glycolysis, the proteome analysis of both HA cell lines showed upregulation of several proteins involved in the regulation of glucose utilization including the active catalytic component of prolyl-4-hydroxylase P4HA1, an important druggable oncogene. HA cell lines demonstrated increased transcription of key regulators of auto-/mitophagy, e.g., neuritin, BCL2 interacting protein 3 (BNIP3), BNIP3-like protein, and BNIP3 pseudogene. Adaptation to hypoxia was further associated with deregulation of apoptosis, namely upregulation of BCL2L1/BCL-XL, overexpression of BCL2L11/BIM, increased binding of BIM to BCL-XL, and significantly increased sensitivity of both HA cell lines to A1155463, a BCL-XL inhibitor. Finally, in both HA cell lines AKT kinase was hyperphosphorylated and the cells showed increased sensitivity to copanlisib, a pan-PI3K inhibitor. In conclusion, our data report on several shared mechanisms of lymphoma cell adaptation to long-term hypoxia including: 1. Upregulation of proteins responsible for glucose utilization, 2. Degradation of mitochondrial proteins for potential mitochondrial recycling (by mitophagy), and 3. Increased dependence on BCL-XL and PI3K-AKT signaling for survival. In translation, inhibition of glycolysis, BCL-XL, or PI3K-AKT cascade may result in targeted elimination of HA lymphoma cells.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":"11 1","pages":"65"},"PeriodicalIF":6.1,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11836139/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143448274","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":"Decreased miR-128-3p in serum exosomes from polycystic ovary syndrome induces ferroptosis in granulosa cells via the p38/JNK/SLC7A11 axis through targeting CSF1.","authors":"Yanqiu Lv, Shengzhong Han, Fuliang Sun, Yuyang Zhang, Xinglin Qu, Hao Li, Weiyu Gu, Qinglong Xu, Shunfa Yao, Xuan Chen, Yi Jin","doi":"10.1038/s41420-025-02331-0","DOIUrl":"10.1038/s41420-025-02331-0","url":null,"abstract":"<p><p>Increasing evidence suggests that non-coding small RNAs (miRNAs) carried by exosomes (EXOs) play important roles in the development and treatment of polycystic ovary syndrome (PCOS). In this study, we demonstrate that PCOS mouse serum-derived EXOs promote granulosa cells (GCs) ferroptosis, and induce the occurrence of a PCOS-like phenotype in vivo. Notably, EXO miRNA sequencing combined with in vitro gain- and loss-of-function assays revealed that miR-128-3p, which is absent in the serum-derived EXOs of mice with PCOS, regulates lipid peroxidation and GC sensitivity to ferroptosis inducers. Mechanistically, overexpression of CSF1, a direct target of miR-128-3p, reversed the anti-ferroptotic effect of miR-128-3p. Conversely, ferroptosis induction was mitigated in CSF1-downregulated GCs. Furthermore, we demonstrated that miR-128-3p inhibition activates the p38/JNK pathway via CSF1, leading to NRF2-mediated down-regulation of SLC7A11 transcription, which triggers GC iron overload. Moreover, intrathecal miR-128-3p AgomiR injection into mouse ovaries ameliorated PCOS-like characteristics and restored fertility in letrozole-induced mice. The study reveals the pathological mechanisms of PCOS based on circulating EXOs and provides the first evidence of the roles of miR-128-3p and CSF1 in ovarian GCs. This discovery is expected to provide promising therapeutic targets for the treatment of PCOS.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":"11 1","pages":"64"},"PeriodicalIF":6.1,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11836375/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143448272","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":"Syk inhibitor attenuates lupus in FcγRIIb^-^/- mice through the Inhibition of DNA extracellular traps from macrophages and neutrophils via p38MAPK-dependent pathway.","authors":"Kritsanawan Sae-Khow, Awirut Charoensappakit, Kanyarat Udompornpitak, Wilasinee Saisorn, Jiraphorn Issara-Amphorn, Tanapat Palaga, Asada Leelahavanichkul","doi":"10.1038/s41420-025-02342-x","DOIUrl":"10.1038/s41420-025-02342-x","url":null,"abstract":"<p><p>Spleen tyrosine kinase (Syk), an important hub of immune signaling, is activated by several signalings in active lupus which could be interfered by Syk inhibitor but is still not completely evaluated in innate immune cells associated with lupus activity. Hence, a Syk inhibitor (fostamatinib; R788) was tested in vivo using Fc gamma receptor-deficient (FcγRIIb^-/-) lupus mice and in vitro (macrophages and neutrophils). After 4 weeks of oral Syk inhibitor, 40 week-old FcγRIIb^-/- mice (a full-blown lupus model) demonstrated less prominent lupus parameters (serum anti-dsDNA, proteinuria, and glomerulonephritis), systemic inflammation, as evaluated by serum TNFa, IL-6, and citrullinated histone H3 (CitH3), gut permeability defect, as indicated by serum FITC dextran assay, serum lipopolysaccharide (LPS), and serum (1 → 3)-β-D-glucan (BG), extracellular traps (ETs) and immune complex deposition in spleens and kidneys (immunofluorescent staining of CitH3 and immunoglobulin G) than FcγRIIb^-/- mice with placebo. Due to the spontaneous elevation of LPS and BG in serum, LPS plus BG (LPS + BG) was used to activate macrophages and neutrophils. After LPS + BG stimulation, FcγRIIb^-/- macrophages and neutrophils demonstrated predominant abundance of phosphorylated Syk (Western blotting), and the pro-inflammatory responses (CD86 flow cytometry analysis, supernatant cytokines, ETs immunofluorescent, and flow cytometry-based apoptosis). With RNA sequencing analysis and western blotting, the Syk-p38MAPK-dependent pathway was suggested as downregulating several inflammatory pathways in LPS + BG-activated FcγRIIb^-/- macrophages and neutrophils. Although both inhibitors against Syk and p38MAPK attenuated macrophage and neutrophil inflammatory responses against LPS + WGP, the apoptosis inhibition by p38MAPK inhibitor was not observed. These results suggested that Syk inhibitor (fostamatinib) improved the severity of lupus caused by FcγRIIb defect partly through Syk-p38MAPK anti-inflammation that inhibited both ET formation and cytokine production from innate immune cells.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":"11 1","pages":"63"},"PeriodicalIF":6.1,"publicationDate":"2025-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11832894/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143440052","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":"CDK8/19 inhibition attenuates G1 arrest induced by BCR-ABL antagonists and accelerates death of chronic myelogenous leukemia cells.","authors":"Alvina I Khamidullina, Margarita A Yastrebova, Alexandra V Bruter, Julia V Nuzhina, Nadezhda E Vorobyeva, Anastasia M Khrustaleva, Ekaterina A Varlamova, Alexander V Tyakht, Iaroslav E Abramenko, Ekaterina S Ivanova, Maria A Zamkova, Jing Li, Chang-Uk Lim, Mengqian Chen, Eugenia V Broude, Igor B Roninson, Alexander A Shtil, Victor V Tatarskiy","doi":"10.1038/s41420-025-02339-6","DOIUrl":"10.1038/s41420-025-02339-6","url":null,"abstract":"<p><p>Imatinib mesylate (IM) and other BCR-ABL tyrosine kinase inhibitors (BCR-ABLi) are the mainstay of chronic myelogenous leukemia (CML) treatment. However, activation of circumventing signaling pathways and quiescence may limit BCR-ABLi efficacy. CDK8/19 Mediator kinases have been implicated in the emergence of non-genetic drug resistance. Dissecting the effects of pharmacological CDK8/19 inhibition on CML survival in response to BCR-ABLi, we found that a selective, non-toxic CDK8/19 inhibitor (CDK8/19i) Senexin B (SenB) and other CDK8/19i sensitized K562 cells to different BCR-ABLi via attenuation of cell cycle arrest. In particular, SenB prevented IM-induced upregulation of genes that negatively regulate cell cycle progression. SenB also antagonized IM-activated p27^Kip1 elevation thereby diminishing the population of G1-arrested cells. After transient G1 arrest, cells treated with IM + SenB re-entered the S phase, where they were halted and underwent replicative stress. Consequently, the combination of IM and SenB intensified apoptotic cell death, measured by activation of caspase 9 and 3, subsequent cleavage of poly(ADPriboso)polymerase 1, positive Annexin V staining and increase of subG1 fraction. In contrast, IM-treated BCR-ABL-positive KU812 CML cells, which did not induce p27^Kip1, readily died regardless of SenB treatment. Thus, CDK8/19i prevent the quiescence-mediated escape from BCR-ABLi-induced apoptosis, suggesting a strategy for avoiding the CML relapse.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":"11 1","pages":"62"},"PeriodicalIF":6.1,"publicationDate":"2025-02-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11830074/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143425177","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":"Cathepsin B prevents cell death by fragmentation and destruction of pathological amyloid fibrils.","authors":"Maksim I Sulatsky, Olesya V Stepanenko, Olga V Stepanenko, Ekaterina V Mikhailova, Anna I Sulatskaya","doi":"10.1038/s41420-025-02343-w","DOIUrl":"10.1038/s41420-025-02343-w","url":null,"abstract":"<p><p>Amyloid fibrils cause organ and tissue dysfunction in numerous severe diseases. Despite the prevalence and severity of amyloidoses, there is still no effective and safe anti-amyloid therapy. This study investigates the impact of cysteine protease cathepsin B (CTSB) on amyloids associated with Alzheimer's and Parkinson's diseases, hemodialysis, and lysozyme amyloidosis. We analyzed the effect of CTSB on the size, structure, and proteotoxicity of amyloid fibrils formed from alpha-synuclein, abeta peptide (1-42), insulin, and lysozyme using a combination of spectroscopic, microscopic, electrophoretic, and colorimetric methods. Our comprehensive research revealed a dual effect of CTSB on amyloid fibrils. Firstly, CTSB induced amyloid fragmentation while preserving their ordered morphology, and, secondly, it \"loosened\" the tertiary structure of amyloids and reduced the regularity of the secondary structure. This dual mechanism of action was universal across fibrils associated with different pathologies, although the disruption efficacy and predominant type of degradation products depended on the amyloids' structure, size, and clustering. Notably, CTSB-induced irreversible degradation significantly reduced the toxicity for immortalized and primary cell lines of low-clustered fibrils, such as alpha-synuclein amyloids associated with Parkinson's disease. These findings enhance our understanding of how endogenous CTSB may regulate amyloid content at the molecular level in different neuropathologies. In addition, our results suggest the potential of CTSB as a component of anti-amyloid drugs in combination with agents that enhance the accessibility of proteolytic sites within amyloid clots and reduce these clusters stability.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":"11 1","pages":"61"},"PeriodicalIF":6.1,"publicationDate":"2025-02-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11830053/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143425176","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":"One-carbon metabolism is distinct metabolic signature for proliferative intermediate exhausted T cells of ICB-resistant cancer patients.","authors":"Ye-Chan Park, Yeseong Hwang, Jae Woong Jeong, Chae Min Lee, Minki Kim, Sugyeong Jo, Seyeon Joo, Nahee Hwang, Sungsoon Fang","doi":"10.1038/s41420-025-02332-z","DOIUrl":"10.1038/s41420-025-02332-z","url":null,"abstract":"<p><p>One-carbon metabolism (1CM) has been reported to promote cancer progression across various malignancies. While 1CM is critical for cell proliferation by enhancing nucleotide synthesis, its physiological roles within different cell types in the tumor immune microenvironment (TIME) still remain unclear. In this study, we analyzed bulk-RNA sequencing and single-cell RNA sequencing (scRNA-seq) data from lung adenocarcinoma (LUAD) patients to elucidate the functional roles of 1CM within the TIME. Moreover, we examined scRNA-seq data from patients treated with immunotherapy across various cancers, including LUAD, glioblastoma, renal cell carcinoma, colorectal cancer, and triple-negative breast cancer. Compared to other cell types, 1CM gene profiles are significantly enriched in a specific subset of T cells. Intriguingly, these high-1CM T cells are identified as proliferative intermediate exhausted T cells (Tex^int). Furthermore, these proliferative Tex^int received the most robust CD137 signaling. Consistently, analysis of scRNA-seq data from LUAD patients undergoing anti-PD1 immunotherapy demonstrated that proliferative Tex^int exhibited higher 1CM scores and increased CD137 signaling. This observation was particularly pronounced in non-responders to immunotherapy, where the Tex^int population was significantly expanded. We further established that 1CM is a prominent signaling pathway in proliferative Tex^int in patients resistant to immunotherapy across multiple cancer types. Collectively, we identify CD137 signaling as a distinctive pathway in proliferative Tex^int of LUAD patients who do not respond to immunotherapy. These findings propose that targeting 1CM may represent a novel therapeutic strategy to enhance the efficacy of immunotherapy by mitigating Tex^int proliferation in diverse cancers.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":"11 1","pages":"60"},"PeriodicalIF":6.1,"publicationDate":"2025-02-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11829039/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143424503","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}