Cell Death and Differentiation最新文献

{"title":"CD95/Fas stoichiometry in future precision medicine","authors":"Mauricio Sica, Murielle Roussel, Patrick Legembre","doi":"10.1038/s41418-025-01493-9","DOIUrl":"https://doi.org/10.1038/s41418-025-01493-9","url":null,"abstract":"<p>CD95, also known as Fas, belongs to the tumor necrosis factor (TNF) receptor superfamily. The main biological function of this receptor is to orchestrate and control the immune response since mutations in CD95 or deregulation of its downstream signaling pathways lead to auto-immunity and inflammation. Interestingly, more than twenty years ago, pioneer studies highlighted that like TNFR1, TRAILR1 or CD40, CD95 pre-associates at the plasma membrane in a ligand-independent fashion. This self-association occurs through a domain designated pre-ligand assembly domain or PLAD. Although the disruption of this pre-association prevents CD95 signaling, no drugs targeting this region have been generated because many questions remain on the stoichiometry and conformation of this receptor. Despite more than 40.000 publications, no crystal structure of CD95 alone or in combination with its ligand, CD95L, exists. Based on other TNFR members, we herein discuss the predicted conformation of CD95 at the plasma membrane and how these putative structures might account for the induction of the cell signaling pathways.</p>","PeriodicalId":9731,"journal":{"name":"Cell Death and Differentiation","volume":"17 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2025-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143831752","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}

{"title":"A novel role of exostosin glycosyltransferase 2 (EXT2) in glioblastoma cell metabolism, radiosensitivity and ferroptosis","authors":"Rocío Matesanz-Sánchez, Mirko Peitzsch, Inga Lange, Jovan Mircetic, Michael Seifert, Nils Cordes, Anne Vehlow","doi":"10.1038/s41418-025-01503-w","DOIUrl":"https://doi.org/10.1038/s41418-025-01503-w","url":null,"abstract":"<p>Glioblastoma (GBM) employs various strategies to resist therapy, resulting in poor patient survival. A key aspect of its survival mechanisms lies in metabolic regulation, maintaining rapid growth and evading cell death. Recent studies revealed the connection between therapy resistance and ferroptosis, a lipid peroxidation-dependent cell death mechanism triggered by metabolic dysfunction. Our aim was to identify novel regulators of therapy resistance in GBM cells. We conducted a comprehensive analysis combining RNA-sequencing data from a panel of human GBM cell models and TCGA GBM patient datasets. We focused on the top-12 differentially expressed gene candidates associated with poor survival in GBM patients and performed an RNA interference-mediated screen to uncover the radiochemosensitizing potential of these molecules and their impact on metabolic activity, DNA damage, autophagy, and apoptosis. We identified exostosin glycosyltransferase 2 (EXT2), an enzyme previously described in heparan sulfate biosynthesis, as the most promising candidate. EXT2 depletion elicited reduced cell viability and proliferation as well as radiochemosensitization in various GBM cell models. Mechanistically, we explored EXT2 function by conducting untargeted and targeted metabolomics and detected that EXT2-depleted GBM cells exhibit a differential abundance of metabolites belonging to S-adenosylmethionine (SAM) metabolism. Considering these metabolic changes, we determined lipid peroxidation and found that the diminished antioxidant capacity resulting from decreased levels of metabolites in the transsulfuration pathway induces ferroptosis. Moreover, modifications of specific SAM and transsulfuration metabolism associated enzymes revealed a prosurvival and ferroptosis-reducing function when EXT2 is depleted. Collectively, our results uncover a novel role of EXT2 in GBM cell survival and response to X-ray radiation, which is controlled by modulation of ferroptosis. These findings expand our understanding of how GBM cells respond to radio(chemo)therapy and may contribute to the development of new therapeutic approaches.</p>","PeriodicalId":9731,"journal":{"name":"Cell Death and Differentiation","volume":"95 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2025-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143836753","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}

{"title":"Targeting the poliovirus receptor to activate T cells and induce myeloid-derived suppressor cells to differentiate to pro-inflammatory macrophages via the IFN-γ-p-STAT1-IRF8 axis in cancer therapy","authors":"Mingyang Feng, Qizhi Ma, Benxia Zhang, Yue Chen, Yang Yang, Xia He, Yao Zeng, Meng Jing, Xuejin Ou, Yixian Liu, Qian Li, Weiting Liao, Xiaoyu Li, Sirui Tan, Diyuan Qin, Dan Li, Qiu Li, Yongsheng Wang","doi":"10.1038/s41418-025-01496-6","DOIUrl":"https://doi.org/10.1038/s41418-025-01496-6","url":null,"abstract":"<p>T cell immunoglobulin and ITIM domain (TIGIT) is one of the most important immune checkpoints expressed on lymphocytes, and poliovirus receptor (PVR, also CD155) serves as the most crucial ligand for TIGIT, harboring an important function in cancer cells and influencing the tumor microenvironment (TME). While it’s well-established that TIGIT blockade could reverse immunosuppression, the question of whether direct inhibition of PVR yields comparable results remains to be fully elucidated. This study investigated the role of PVR within the TME on the LLC, CT26 and MC38 tumor models and found that direct blockade of PVR on tumor cells could trigger T cell activation, enhance the production of immunostimulatory cytokine IFN-γ, and drive the differentiation of intratumoral myeloid-derived suppressor cells (MDSCs) into pro-inflammatory macrophages through the IFN-γ-p-STAT1-IRF8 axis. Furthermore, this study found that the anti-PVR nanobody monotherapy reduced tumor volume in the CT26 and MC38 tumor models. Combination of anti-PVR nanobody and anti-PD-1 antibody was effective in the LLC, CT26 and MC38 tumor models and had acceptable toxicity. These findings collectively suggest that PVR exhibits considerable promise as a therapeutic target in the development of immunotherapies aimed at augmenting the anti-tumor immune response.</p>","PeriodicalId":9731,"journal":{"name":"Cell Death and Differentiation","volume":"108 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2025-04-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143827666","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}

{"title":"Glycogen stores mediated by the p53-GYS1 feedback circuit engenders platinum resistance in ovarian clear cell carcinoma","authors":"Hao-Yu Liang, Rong-Zhen Luo, Ru Deng, Shi-Lu Chen, Xuan Liu, Xia Yang, Li-Jun Wei, Zong-Qiang Wei, Li-Yan Wu, Hui-Min Shen, Jing-Ping Yun, Li-Li Liu","doi":"10.1038/s41418-025-01500-z","DOIUrl":"https://doi.org/10.1038/s41418-025-01500-z","url":null,"abstract":"<p>Ovarian cancer (OC) is a highly fatal and refractory malignancy affecting women, and platinum resistance remains a major clinical dilemma. Compared with other OC subtypes, ovarian clear cell carcinoma (OCCC) frequently exhibits increased platinum refractoriness, accompanied by increased glycogen levels, which promotes clear-cell morphology, and wild-type p53. However, the roles of these factors in platinum resistance of OCCC are unclear. Here, we investigated whether glycogen promotes OCCC resistance to platinum agents and reported that GYS1, a rate-limiting enzyme in glycogen synthesis, is clinically associated with poor prognosis and chemoresistance in OCCC. Mechanistically, p53 promotes GYS1 breakdown via the upregulation of RNF144a, whereas GYS1 induces the reversal of p53 ubiquitination and degradation by competitively binding to USP14, forming a positive feedback circuit. Under platinum stress, the accumulated glycogen is mobilized by the p53/GYS1 feedback circuit, which fuels energetic NADPH production, resulting in resistance to disulfidptosis and increased platinum resistance in OCCC. Collectively, our findings identify glycogen as a contributor to OCCC platinum resistance and elucidate the underlying mechanisms, highlighting a crucial p53/GYS1 positive feedback loop.</p>","PeriodicalId":9731,"journal":{"name":"Cell Death and Differentiation","volume":"183 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2025-04-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143819554","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}

{"title":"Chronic skin and systemic inflammation modulated by S100A8 and S100A9 complexes","authors":"Marta Palomo-Irigoyen, Latifa Bakiri, Tim Hendrikx, Silvia Hayer, Johanna Schaffenrath, Stefanie Widder, Sandra Bachg, Jared Simmons, Richard L. Gallo, Philipp Starkl, Johannes Roth, Erwin F. Wagner","doi":"10.1038/s41418-025-01504-9","DOIUrl":"https://doi.org/10.1038/s41418-025-01504-9","url":null,"abstract":"<p>Increased expression of the homodimeric S100A8 (A8) and S100A9 (A9) alarmins and their Calprotectin (CP) antimicrobial hetero-complex has been reported in Inflammatory Skin Diseases (ISDs) such as Atopic Dermatitis (AD), but the functional consequences of this increase are not known. We evaluated the cell- and tissue-specific functions of A8 and A9 in the local and the extra-cutaneous manifestations of ISD using genetically engineered mouse models. The genes encoding for the A9 or A8 proteins were inactivated in epidermal cells or neutrophils in the <i>JunB</i>^<i>∆ep</i> genetic mouse model for AD. Overall, epidermal inactivation of <i>A9</i> aggravated, while similar <i>A8</i> inactivation ameliorated experimental ISD. Epidermal differentiation and skin inflammation was also ameliorated when <i>A9</i> was inactivated in neutrophils or in all cells. However, complete <i>A9</i> knock-out was associated with worsened systemic effects, such as neutrophilic inflammation and bone loss. In addition, the distal phalanges of the digits displayed increased A8 protein expression, SA overgrowth and bone destruction. Epidermal <i>A8</i> inactivation ameliorated bone loss, but promoted bone destruction in the digits, likely through A8-positive neutrophilic infiltrates. These data show that site- and cell-type-specific A8 and A9 expression modulates chronic skin and systemic inflammation with distinct effects on the skin differentiation and on the musculoskeletal system. These findings pave the way for novel therapies targeting the divergent functions of A8 and A9 to restore epidermal homeostasis and prevent systemic complications.</p><figure></figure>","PeriodicalId":9731,"journal":{"name":"Cell Death and Differentiation","volume":"8 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2025-04-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143822710","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}

{"title":"ZNF593 regulates the cGAS-mediated innate immune response by attenuating cGAS-DNA binding","authors":"Xuemei Bai, Na Dong, Nan Cao, Min Zhou, Jiahua Yuan, Yuling Zhang, Yaxing Liu, JiaJia Zhang, Tian Chen, Feng Liu, Wanwei Sun, Yi Zheng, Wei Zhao, Qiang Shu, Chengjiang Gao, Bingyu Liu","doi":"10.1038/s41418-025-01508-5","DOIUrl":"https://doi.org/10.1038/s41418-025-01508-5","url":null,"abstract":"<p>The enzyme cyclic GMP-AMP synthase (cGAS) is essential for detecting aberrantly located double-stranded DNA (dsDNA) from genomic, mitochondrial, and microbial origins. Through the synthesis of 2′3′-cGAMP, cGAS triggers the activation of the stimulator of interferon genes pathway, which initiates in vivo innate immune responses. Here, we identify zinc finger proteins ZNF593, which translocate from the nucleus to the cytoplasm after viral infection, as a negative regulator of antiviral type I IFN (IFN-I) production. ZNF593 directly binds to cGAS and suppresses its activation by inhibiting the cGAS-dsDNA interaction. ZNF593 deficiency increases IRF3 nuclear translocation and promotes DNA virus-triggered IFN production. Furthermore, ZNF593 deficiency promotes antiviral innate responses in vivo, improving survival rates in mice against HSV-1 infection. We further find that ZNF593 plays a protective role in systemic lupus erythematosus (SLE) pathology. Notably, replenishing ZNF593 effectively reduced IFN production in peripheral blood mononuclear cells (PBMCs) of SLE patients or in the TMPD-induced murine SLE model. Our findings suggest that ZNF593 negatively regulates IFN-β signaling by targeting cGAS activation, providing new insights into the regulatory mechanisms for antiviral defenses and autoimmune diseases.</p>","PeriodicalId":9731,"journal":{"name":"Cell Death and Differentiation","volume":"60 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2025-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143819555","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}

{"title":"Formyl peptide receptor 1 and its antagonist T0080 in atherosclerosis","authors":"Yu-Jing Li, Xue Zhao, Siting Wu, Nan Yao, Xueyu Zhang, Yanyan Liu, Xiaobing Tian, Yulin Li, Bin Gao, S. Claiborne Johnston, Fu-Dong Shi, Zhiguo Li","doi":"10.1038/s41418-025-01506-7","DOIUrl":"https://doi.org/10.1038/s41418-025-01506-7","url":null,"abstract":"<p>Focal inflammation and arterial damage driven by macrophages are key pathogenic processes in atherosclerosis. However, the mechanisms that regulate these processes remain poorly understood. In this study, we demonstrate that formyl peptide receptor 1 (FPR1) agonist, a mitochondrial N-formyl peptide, is elevated in the blood of patients with atherosclerosis and correlates with carotid stenosis. Macrophages expressing FPR1 were found in atherosclerotic lesions. Conditional deletion of <i>Fpr1</i> in macrophages reduced plaque formation, local inflammation, and aortic atherosclerosis in apolipoprotein E (<i>ApoE</i>)^−/− mice. FPR1 activates protein kinase C (PKC) in macrophages, promoting the production of reactive oxygen species (ROS), tumor necrosis factor alpha (TNF-α) and interleukin-1beta (IL-1β), which accelerates the apoptosis of endothelial cells and smooth muscle cells. To inhibit FPR1 bioactivity, we developed an antagonist, T0080. Therapeutic administration of T0080 attenuates atherosclerotic progression in <i>ApoE</i>^−/− mice. Our findings highlight the pivotal role of FPR1 in macrophage-mediated atherosclerotic plaque formation and support further investigation of T0080-mediated FPR1 inhibition as a potential treatment for atherosclerosis.</p>","PeriodicalId":9731,"journal":{"name":"Cell Death and Differentiation","volume":"97 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2025-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143805695","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}

{"title":"Enhancement of colorectal cancer therapy through interruption of the HSF1-HSP90 axis by p53 activation or cell cycle inhibition","authors":"Tamara Isermann, Kim Lucia Schneider, Florian Wegwitz, Tiago De Oliveira, Lena-Christin Conradi, Valery Volk, Friedrich Feuerhake, Björn Papke, Sebastian Stintzing, Bettina Mundt, Florian Kühnel, Ute M. Moll, Ramona Schulz-Heddergott","doi":"10.1038/s41418-025-01502-x","DOIUrl":"https://doi.org/10.1038/s41418-025-01502-x","url":null,"abstract":"<p>The stress-associated chaperone system is an actionable target in cancer therapies. It is ubiquitously upregulated in cancer tissues and enables tumorigenicity by stabilizing oncoproteins. Most inhibitors target the key component, heat-shock protein 90 (HSP90). Although HSP90 inhibitors are highly tumor-selective, they fail in clinical trials. These failures are partly due to interference with a negative regulatory feedback loop in the heat-shock response (HSR): in response to HSP90 inhibition, there is compensatory synthesis of stress-inducible chaperones, mediated by the transcription factor heat-shock-factor 1 (HSF1). We recently identified that wild-type p53 reduces the HSR by repressing HSF1 via a p21-CDK4/6-MAPK-HSF1 axis. Here, we test whether in HSP90-based therapies, simultaneous p53 activation or direct cell cycle inhibition interrupts the deleterious HSF1-HSR axis and improves the efficiency of HSP90 inhibitors. We found that the clinically relevant p53 activator Idasanutlin suppresses the HSF1-HSR activity in HSP90 inhibitor-based therapies. This combination synergistically reduces cell viability and accelerates cell death in p53-proficient colorectal cancer (CRC) cells, murine tumor-derived organoids, and patient-derived organoids (PDOs). Mechanistically, upon combination therapy, CRC cells upregulate p53-associated pathways, apoptosis, and inflammatory pathways. Likewise, in a CRC mouse model, dual HSF1-HSP90 inhibition represses tumor growth and remodels immune cell composition. Importantly, inhibition of the cyclin-dependent kinases 4/6 (CDK4/6) under HSP90 inhibition phenocopies synergistic repression of the HSR in p53-proficient CRC cells. Moreover, in p53-deficient CRC cells, HSP90 inhibition in combination with CDK4/6 inhibitors similarly suppresses the HSF1-HSR and reduces cancer growth. Likewise, p53-mutated PDOs respond to dual HSF1-HSP90 inhibition, providing a strategy to target CRC independent of the p53 status. In sum, we provide new options to improve HSP90-based therapies to enhance CRC therapies.</p>","PeriodicalId":9731,"journal":{"name":"Cell Death and Differentiation","volume":"75 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2025-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143813769","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}

{"title":"The BCL-2 protein family: from discovery to drug development","authors":"Carlo M. Croce, David Vaux, Andreas Strasser, Joseph T. Opferman, Peter E. Czabotar, Stephen W. Fesik","doi":"10.1038/s41418-025-01481-z","DOIUrl":"https://doi.org/10.1038/s41418-025-01481-z","url":null,"abstract":"<p>The landmark discovery of the BCL-2 gene and then its function marked the identification of inhibition of apoptotic cell death as a crucial novel mechanism driving cancer development and launched the quest to discover the molecular control of apoptosis. This work culminated in the generation of specific inhibitors that are now in clinical use, saving and improving tens of thousands of lives annually. Here, some of the original players of this story, describe the sequence of critical discoveries. The t(14;18) chromosomal translocation, frequently observed in follicular lymphoma, allowed the identification and the cloning of a novel oncogene (<i>BCL-2</i>) juxtaposed to the immunoglobulin heavy chain gene locus (<i>IgH</i>). Of note, BCL-2 acted in a distinct manner as compared to then already known oncogenic proteins like ABL and c-MYC. BCL-2 did not promote cell proliferation but inhibited cell death, as originally shown in growth factor dependent haematopoietic progenitor cell lines (e.g., FDC-P1) and in <i>Eμ-Myc/Eμ-Bcl-2</i> double transgenic mice. Following a rapid expansion of the BCL-2 protein family, the Abbott Laboratories solved the first structure of BCL-XL and subsequently the BCL-XL/BAK peptide complex, opening the way to understanding the structures of other BCL-2 family members and, finally, to the generation of inhibitors of the different pro-survival BCL-2 proteins, thanks to the efforts of Servier/Norvartis, Genentech/WEHI, AbbVie, Amgen, Prelude and Gilead. Although the BCL-2 inhibitor Venetoclax is in clinical use and inhibitors of BCL-XL and MCL-1 are undergoing clinical trials, several questions remain on whether therapeutic windows can be achieved and what other agents should be used in combination with BH3 mimetics to achieve optimal therapeutic impact for cancer therapy. Finally, the control of the expression of BH3-only proteins and pro-survival BCL-2 family members needs to be better understood as this may identify novel targets for cancer therapy. This story is still not concluded!</p>","PeriodicalId":9731,"journal":{"name":"Cell Death and Differentiation","volume":"183 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2025-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143813770","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}

{"title":"p53 transcriptionally activates DCP1B to suppress tumor progression and enhance tumor sensitivity to PI3K blockade in non-small cell lung cancer","authors":"Shiqi Chen, Qian Hao, Yu Gan, Jing Tong, Chen Xiong, Quan Liao, Yang Zhang, Ting Ye, Xiang Zhou, Haiquan Chen","doi":"10.1038/s41418-025-01501-y","DOIUrl":"https://doi.org/10.1038/s41418-025-01501-y","url":null,"abstract":"<p>Non-small cell lung cancer (NSCLC), which accounts for approximately 85% of lung cancer patients, is characterized by its aggressive nature and poor prognosis. In this study, we identify decapping mRNA 1B (<i>DCP1B</i>) as a tumor suppressor gene that is transcriptionally regulated by p53. DCP1B is found to inhibit the growth and migration of NSCLC cells. Consistently, the level of DCP1B expression is decreased in NSCLC tissues, and its low expression is associated with NSCLC patients’ unfavorable outcomes. Mechanistic investigations reveal that DCP1B promotes the turnover of mitogen-activated protein kinase 4 (<i>MAPK4</i>) mRNA, and the activation of p53 reduces the expression level of MAPK4 partially through DCP1B. Notably, overexpression of MAPK4 can drive AKT phosphorylation independent of phosphoinositide 3-kinase (PI3K), thus neutralizing the anti-tumor activity of the PI3K inhibitor in NSCLC cells. Moreover, the p53 agonist combined with the PI3K inhibitor can suppress NSCLC proliferation synergistically in vitro and in vivo. Collectively, this study not only uncovers the function and mechanism of the p53-DCP1B-MAPK4 axis in suppressing NSCLC progression but also suggests a promising combination strategy for treating NSCLC.</p>","PeriodicalId":9731,"journal":{"name":"Cell Death and Differentiation","volume":"14 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2025-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143805692","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}