Cell Death & Disease最新文献_第2页

mTOR inhibition enhances the antitumor efficacy of pan-RAF-MEK blockade by inhibiting the ATF4-MTHFD2 pathway. mTOR抑制通过抑制ATF4-MTHFD2通路增强了pan-RAF-MEK阻断的抗肿瘤效果。

IF 9.6 1区生物学

Cell Death & Disease Pub Date : 2026-05-06 DOI: 10.1038/s41419-026-08836-5

Feiyang Cai, Fan Huang, Christophe Goncalves, Harinee Srikannan, Natascha Gagnon, Elizabeth M Guettler, Léa Mukeba-Harchies, Jennifer Maxwell, Jie Su, Krikor Bijian, Fabrice Journe, April A N Rose, Alexandre Orthwein, Sonia Victoria Del Rincón, Wilson H Miller

{"title":"mTOR inhibition enhances the antitumor efficacy of pan-RAF-MEK blockade by inhibiting the ATF4-MTHFD2 pathway.","authors":"Feiyang Cai, Fan Huang, Christophe Goncalves, Harinee Srikannan, Natascha Gagnon, Elizabeth M Guettler, Léa Mukeba-Harchies, Jennifer Maxwell, Jie Su, Krikor Bijian, Fabrice Journe, April A N Rose, Alexandre Orthwein, Sonia Victoria Del Rincón, Wilson H Miller","doi":"10.1038/s41419-026-08836-5","DOIUrl":"https://doi.org/10.1038/s41419-026-08836-5","url":null,"abstract":"BRAF V600 inhibitors are clinically approved for the treatment of BRAFV600-mutant melanoma in combination with a MEK inhibitor, but are ineffective in other melanoma subtypes. Moreover, pan-RAF inhibitors, such as belvarafenib, when combined with MEK inhibitors (cobimetinib), have promising but limited efficacy in non-BRAF-mutant melanomas. Here, we report that the mTOR inhibitor sapanisertib improves the efficacy of combined belvarafenib and cobimetinib therapy in NRAS, NF1, and KIT-mutant melanomas. Mechanistically, sapanisertib combined with belvarafenib and cobimetinib suppressed ATF4 expression and its target gene MTHFD2 while inducing DNA damage, revealing a previously underappreciated role of the ATF4-MTHFD2 axis in DNA damage repair and drug response. Human and murine models resistant to combined belvarafenib and cobimetinib exhibited elevated levels of ATF4 and MTHFD2 and were sensitive to sapanisertib. This study provides promising treatment opportunities for patients with non-BRAF-mutant melanomas, or those who relapse following belvarafenib and cobimetinib combination therapy.","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":" ","pages":""},"PeriodicalIF":9.6,"publicationDate":"2026-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147834268","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Six1 haploinsufficiency is associated with activation of NF-κB and TNF-related transcriptional signatures in aging mice. Six1单倍不足与衰老小鼠NF-κB和tnf相关转录特征的激活有关。

IF 9.6 1区生物学

Cell Death & Disease Pub Date : 2026-05-06 DOI: 10.1038/s41419-026-08831-w

Tianxu Guo, Han Liu, Junjun Ma, Huanyu Yan, Yanglin Chen, Lihua Zhao, Xiyun Guo, Limin Lv, Yixi Wang, Linxin Cheng, Guang Yang, Yu Zhang, Jinbo Yu, Xi Wang, Shuguang Duo, Xihe Li, Rongfeng Li

{"title":"Six1 haploinsufficiency is associated with activation of NF-κB and TNF-related transcriptional signatures in aging mice.","authors":"Tianxu Guo, Han Liu, Junjun Ma, Huanyu Yan, Yanglin Chen, Lihua Zhao, Xiyun Guo, Limin Lv, Yixi Wang, Linxin Cheng, Guang Yang, Yu Zhang, Jinbo Yu, Xi Wang, Shuguang Duo, Xihe Li, Rongfeng Li","doi":"10.1038/s41419-026-08831-w","DOIUrl":"https://doi.org/10.1038/s41419-026-08831-w","url":null,"abstract":"The Six1 (SIX homeobox 1) gene is pivotal in renal and pulmonary development and differentiation. Its dysregulation is implicated in oncogenesis and tumor progression via enhancing cell proliferation and delaying senescence. However, whether or how it functions in the natural aging have not been investigated. To answer this question, we generated Six1 gene knockout mice using CRISPR-Cas9 technology. All Six1 biallelic knockout mice died at birth since the underdeveloped lungs. In Six1+/- mice, the developmental deficiencies in kidneys with vacuolar degeneration and epithelial disruption in renal tubules, as well as hematopoietic interstitial infiltration and lungs with interstitial condensation and alveolar hypoplasia were observed. These developmental deficiencies persist with age and age-dependent phenotypes become more pronounced in Six1+/- mice compared to the wild-type, with upregulation of senescence markers (p16, p53) and senescence-associated secreted factors (e.g., TNF-α, TIMP-2), increased α-SMA expression and collagen deposition, as well as susceptibility to pulmonary fibrosis. Transcriptomic sequencing coupled with bioinformatics analysis indicated that genes with altered expression in Six1+/- mouse lungs showed enrichment in pathways associated with senescence, including the NF-κB and TNF signaling pathways. These transcriptional patterns were also associated with gene sets involved in mitochondrial metabolic processes. Collectively, these findings suggest that Six1 haploinsufficiency is associated with transcriptional signatures linked to aging-related pathways under physiological conditions in mice, providing potential clues for future studies exploring mechanisms of aging.","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":" ","pages":""},"PeriodicalIF":9.6,"publicationDate":"2026-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147834292","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Inhibition of Pellino-1 reverts the progression and tyrosine kinase inhibitor resistance in chronic myeloid leukemia. 抑制Pellino-1可逆转慢性髓性白血病的进展和酪氨酸激酶抑制剂耐药性。

IF 9.6 1区生物学

Cell Death & Disease Pub Date : 2026-05-05 DOI: 10.1038/s41419-026-08799-7

Qian Zhou, Guangsen Xu, Zhuoran Li, Yan Xu, Jianmin Guan, Zhenyu Li, Mingying Li, Tingjian Zu, Yuan Li, Chunhua Lu, Chunyan Ji, Baobing Zhao

{"title":"Inhibition of Pellino-1 reverts the progression and tyrosine kinase inhibitor resistance in chronic myeloid leukemia.","authors":"Qian Zhou, Guangsen Xu, Zhuoran Li, Yan Xu, Jianmin Guan, Zhenyu Li, Mingying Li, Tingjian Zu, Yuan Li, Chunhua Lu, Chunyan Ji, Baobing Zhao","doi":"10.1038/s41419-026-08799-7","DOIUrl":"https://doi.org/10.1038/s41419-026-08799-7","url":null,"abstract":"BCR-ABL1, derived from structural chromosome rearrangements, is the driver mutation in chronic myeloid leukemia (CML). Targeting BCR-ABL1 for degradation is an ideal therapeutic strategy for CML, however, the regulatory mechanisms controlling BCR-ABL1 expression in CML remained unclear. Here, we identified PELI1 as a key regulator for maintaining BCR-ABL1 in CML. BCR-ABL1 upregulates PELI1 via the STAT5/FOXP3 pathway, and the increased PELI1 then interacts with and protects BCR-ABL1 from degradation in CML cells. Concurrently, PELI1 functions as a downstream effector to promote CML cell proliferation. Notably, genetic or pharmacological inhibition of PELI1 effectively suppresses the proliferation of both tyrosine kinase inhibitors (TKIs)-sensitive and TKI-resistant CML cells, as well as Leukemia stem cells (LSCs), which consequently ameliorates the disease burden and progression of CML. Collectively, our findings demonstrated that targeting PELI1 is a promising therapeutic strategy for CML that can overcome TKI resistance and eliminates LSCs.","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":" ","pages":""},"PeriodicalIF":9.6,"publicationDate":"2026-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147834313","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Correction: Retrograde transport of neurotrophin receptor TrkB-FL induced by excitotoxicity regulates Golgi stability and is a target for stroke neuroprotection. 更正：兴奋毒性诱导的神经营养因子受体TrkB-FL逆行转运调节高尔基稳定性，是卒中神经保护的靶点。

IF 9.6 1区生物学

Cell Death & Disease Pub Date : 2026-05-05 DOI: 10.1038/s41419-026-08785-z

Gema María Esteban-Ortega, Elena Torres-Campos, Margarita Díaz-Guerra

引用次数: 0

Correction: The m6A reader HNRNPC promotes glioma progression by enhancing the stability of IRAK1 mRNA through the MAPK pathway. 更正：m6A读取器HNRNPC通过MAPK途径增强IRAK1 mRNA的稳定性，从而促进胶质瘤的进展。

IF 9.6 1区生物学

Cell Death & Disease Pub Date : 2026-05-05 DOI: 10.1038/s41419-026-08775-1

Jun-Jun Chen, Tian-Zhu Lu, Tao Wang, Wen-Hui Yan, Fang-Yan Zhong, Xin-Hui Qu, Xiao-Chang Gong, Jin-Gao Li, Fang-Fang Tou, Li-Ping Jiang, Xiao-Jian Han

引用次数: 0

Correction: SLC7A11 upregulation via AR and NEDD4L ubiquitination contributes to ferroptosis inhibition and enzalutamide resistance in castration-resistant prostate cancer. 更正：SLC7A11通过AR和NEDD4L泛素化上调有助于去势抵抗性前列腺癌的铁凋亡抑制和恩杂鲁胺耐药。

IF 9.6 1区生物学

Cell Death & Disease Pub Date : 2026-05-05 DOI: 10.1038/s41419-026-08741-x

Min Tang, Luotong Xue, Bao Wang, Zhixin Jiang, Pu Li, Hengtao Bu, Chesong Zhao, Yurong Zhang, Shuaimei Liu, Xiyuan Chen, Bianjiang Liu, Xiaoxin Meng, Jie Li

引用次数: 0

Granulocyte differentiation arrest in HAX1-deficient cells, demonstrated in a new in vitro model of a certain phenotypic aspects of Kostmann disease, is caused by ineffective lipid droplet autophagy and fatty acids uptake. 在Kostmann病某些表型方面的新的体外模型中，hax1缺陷细胞的粒细胞分化停滞是由脂滴自噬和脂肪酸摄取无效引起的。

IF 9.6 1区生物学

Cell Death & Disease Pub Date : 2026-05-05 DOI: 10.1038/s41419-026-08805-y

Maciej Wakula, Milena Jablonowska, Mateusz Chmielarczyk, Leszek Tarnowski, Mariusz Kulinczak, Ewa Sitkiewicz, Bianka Swiderska, Emilia Samborowska, Mariusz Radkiewicz, Mostafa Kianfar, Malgorzata Statkiewicz, Izabela Rumienczyk, Anna Balcerak, Ryszard Konopinski, Alicja Trebinska-Stryjewska, Ewa A Grzybowska

{"title":"Granulocyte differentiation arrest in HAX1-deficient cells, demonstrated in a new in vitro model of a certain phenotypic aspects of Kostmann disease, is caused by ineffective lipid droplet autophagy and fatty acids uptake.","authors":"Maciej Wakula, Milena Jablonowska, Mateusz Chmielarczyk, Leszek Tarnowski, Mariusz Kulinczak, Ewa Sitkiewicz, Bianka Swiderska, Emilia Samborowska, Mariusz Radkiewicz, Mostafa Kianfar, Malgorzata Statkiewicz, Izabela Rumienczyk, Anna Balcerak, Ryszard Konopinski, Alicja Trebinska-Stryjewska, Ewa A Grzybowska","doi":"10.1038/s41419-026-08805-y","DOIUrl":"https://doi.org/10.1038/s41419-026-08805-y","url":null,"abstract":"Molecular mechanisms underlying congenital neutropenia in patients with HAX1 deficiency are not clear at the moment. HAX1 deficiency was shown to result in the arrest of neutrophil differentiation. Our studies of the effect of HAX1 deficiency on the proteomic and metabolic profiles of promyelocytic cells have led to the conclusion, supported by specific tests, that fatty acid metabolism is affected in HAX1 KO cells. The lipid droplet content is increased in HAX1 KO cells, pointing to the accumulation of fatty acids that are not metabolized. Studies of autophagosome function in HAX1 WT and KO cells revealed that lipid droplet autophagy is defective at the stage of fusion with the lysosome. Autophagy-dependent generation of free fatty acids is critical for neutrophil differentiation, so HAX1 deficiency that affects normal autophagy of lipids in promyeloblasts should explain differentiation arrest. Moreover, we have demonstrated that HAX1-deficient cells are also compromised in fatty acid uptake.","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":" ","pages":""},"PeriodicalIF":9.6,"publicationDate":"2026-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147834297","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

IF 9.6 1区生物学

Cell Death & Disease Pub Date : 2026-05-05 DOI: 10.1038/s41419-026-08773-3

Xianwen Wang, Qihang Huang, Zhihong Zuo, Zhanwen Wang, Lina Zhang, Zhaoxin Qian

{"title":"Age-related differences and common pathways of lymphocyte subsets in sepsis: a comparative review of elderly and pediatric patients.","authors":"Xianwen Wang, Qihang Huang, Zhihong Zuo, Zhanwen Wang, Lina Zhang, Zhaoxin Qian","doi":"10.1038/s41419-026-08773-3","DOIUrl":"https://doi.org/10.1038/s41419-026-08773-3","url":null,"abstract":"Sepsis disproportionately affects older adults and children, two immunologically vulnerable extremes of age. Yet sepsis is superimposed on distinct baselines-immunosenescence in the elderly and immune immaturity in neonates and young children-leading to different pathways toward immune failure. This comparative narrative review synthesizes clinical and experimental evidence on age-specific and shared alterations in lymphocyte subsets in sepsis, including lymphopenia; CD4+ and CD8+ T cell activation, apoptosis, and exhaustion; B cell depletion and impaired antibody production; NK cell cytotoxic defects; and dynamic regulatory circuits such as Tregs. Recognizing that early organ injury is initiated and amplified primarily by innate immune programs, we frame lymphocyte injury largely as a downstream cost of the acute host-response milieu that can become rate-limiting for immune recovery, secondary infections, and late mortality. We highlight convergent phenotypes linked to secondary infections and late mortality, while emphasizing differences in kinetics, mechanisms, and recovery potential. We propose an age-stratified approach to serial immune monitoring and biomarker-enriched trial design to guide immunoadjuvant therapies and avoid one-size-fits-all immunomodulation. Clarifying these trajectories may improve risk stratification and outcomes across the lifespan.","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":" ","pages":""},"PeriodicalIF":9.6,"publicationDate":"2026-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147834333","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Multi-omics reveals CXCR4 drives immune escape in colorectal cancer via metabolic reprogramming and immune microenvironment remodeling. 多组学揭示CXCR4通过代谢重编程和免疫微环境重塑驱动结直肠癌的免疫逃逸。

IF 9.6 1区生物学

Cell Death & Disease Pub Date : 2026-05-04 DOI: 10.1038/s41419-026-08795-x

Chengle Zhu, Yuting Liu, Shaopeng Xu, Ruonan Li, Jiwen Shi, Guohui Tang, Ruorong Ran, Bo Pang, Zixiang Chi, Yongxing Ding, Wenrui Wang, Qingling Yang, Changjie Chen

{"title":"Multi-omics reveals CXCR4 drives immune escape in colorectal cancer via metabolic reprogramming and immune microenvironment remodeling.","authors":"Chengle Zhu, Yuting Liu, Shaopeng Xu, Ruonan Li, Jiwen Shi, Guohui Tang, Ruorong Ran, Bo Pang, Zixiang Chi, Yongxing Ding, Wenrui Wang, Qingling Yang, Changjie Chen","doi":"10.1038/s41419-026-08795-x","DOIUrl":"https://doi.org/10.1038/s41419-026-08795-x","url":null,"abstract":"Colorectal cancer (CRC) is one of the most common malignant tumors with the highest incidence and mortality rates worldwide. Immune checkpoint blockade (ICB) therapy has revolutionized the landscape of cancer treatment; however, most patients with CRC gain limited benefits from it. The immunosuppressive microenvironment of CRC is an important cause of tumor progression, metastasis, and immunotherapy resistance. This study aimed to reveal the key role of chemokine receptor 4 (CXCR4) in the immunosuppressive microenvironment and glutamine metabolism reprogramming using integrated single-cell transcriptomics and metabolomics analyses. The in vivo and in vitro experiments verified that CXCR4 mediated metabolic reprogramming in CRC cells by regulating the PI3K-Akt-SMAD4 pathway. Further co-culture experiments revealed that CXCR4 promoted the polarization of tumor-associated macrophages (TAMs) to M2 type through glutamine metabolic reprogramming and induced the exhaustion of CD8+ T cells, thereby intensifying immune escape. The knockdown of CXCR4 significantly increased the infiltration of CD8+ T cells and M1 TAMs, reduced the infiltration of M2 TAMs, effectively reshaped the immunosuppressive microenvironment of CRC-bearing mice, and significantly enhanced the immunotherapeutic effect against programmed cell death protein 1 (PD-1). This study discovered a novel mechanism by which CXCR4 drove CRC immune escape through the dual-axis regulation of the \"glutamine metabolism-immune microenvironment.\" Targeting CXCR4 not only inhibits tumor metabolic adaptability but also reverses TAMs polarization and T cell exhaustion, thereby effectively sensitizing PD-1 inhibitors. This study provides an important theoretical basis and a highly promising new combined treatment strategy for overcoming ICB resistance in patients with CRC.","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":" ","pages":""},"PeriodicalIF":9.6,"publicationDate":"2026-05-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147834264","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

RILPL2 suppresses metabolic reprogramming and progression of cervical cancer by attenuating LDHA protein stability and inhibiting H3K18 lactylation. RILPL2通过降低LDHA蛋白稳定性和抑制H3K18乳酸化抑制宫颈癌的代谢重编程和进展。

IF 9.6 1区生物学

Cell Death & Disease Pub Date : 2026-05-04 DOI: 10.1038/s41419-026-08808-9

Yujing Shi, Zhaoyue Zhang, Jin Liu, Caiqiang Zhu, Gefenqiang Shen, Meng Tian, Liang Liang, Jinhui Liu, Xiaoke Di

{"title":"RILPL2 suppresses metabolic reprogramming and progression of cervical cancer by attenuating LDHA protein stability and inhibiting H3K18 lactylation.","authors":"Yujing Shi, Zhaoyue Zhang, Jin Liu, Caiqiang Zhu, Gefenqiang Shen, Meng Tian, Liang Liang, Jinhui Liu, Xiaoke Di","doi":"10.1038/s41419-026-08808-9","DOIUrl":"https://doi.org/10.1038/s41419-026-08808-9","url":null,"abstract":"Cervical cancer (CC) is a prevalent malignancy among women worldwide with considerable incidence and mortality. Recent studies have suggested that the Rab-interacting lysosomal protein-like 2 (RILPL2) acts as a tumor suppressor and plays an inhibitory role in multiple human cancers. However, the potential effect of RILPL2 in CC remains unclear. In our investigation, we found that RILPL2 was downregulated in CC samples and was associated with a favorable outcome. Further findings indicated the interaction between RILPL2 and lactate dehydrogenase A (LDHA), a crucial player regulating glycolysis. Mechanistically, RILPL2 reduced LDHA stability by recruiting TRIM21 to facilitate K48-linked ubiquitination chains of LDHA and promoting LDHA degradation, thereby blocking glycolytic reprogramming and, in turn, inhibiting CC progression and development. Moreover, RILPL2-mediated inhibition of the glycolytic pathway could restrain lactate production, which abolished H3K18 lactylation to induce the downregulation of SOX9 and SMYD2. Consequently, our results suggested that RILPL2 may serve as a potential therapeutic target for the treatment of CC.","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":" ","pages":""},"PeriodicalIF":9.6,"publicationDate":"2026-05-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147834329","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0