Cell Death Discovery最新文献

{"title":"Targeting serine/glycine metabolism to attenuate IFN-γ- and IL-22-driven inflammation and hyperproliferation in psoriasis.","authors":"Laura Mercurio, Valentina Di Francesco, Simone Sergio, Martina Morelli, Claudia Scarponi, Stefania Madonna, Sabatino Pallotta, Mara Mancini, Angela Cappello, Eleonora Candi, Cristina Albanesi","doi":"10.1038/s41420-026-03138-3","DOIUrl":"https://doi.org/10.1038/s41420-026-03138-3","url":null,"abstract":"<p><p>Psoriasis is a chronic skin disease characterized by keratinocyte hyperproliferation and inflammation, largely driven by the cytokines IL-22 and interferon (IFN)-γ. These cytokines activate the signal transducer and activator of transcription (STAT) 3 and STAT1 molecular pathways, leading to abnormal proliferation, impaired differentiation, and increased production of inflammatory mediators in keratinocytes. While the IL-22/STAT3 pathway primarily promotes de-differentiation in keratinocytes, IFN-γ/STAT1-3 signaling induces pronounced inflammation, despite exerting antiproliferative effects on these cells. Recent research has highlighted the role of serine/glycine metabolism in the pathogenesis of psoriasis, by supporting T cell and keratinocyte proliferation. Furthermore, pharmacological inhibition of serine catabolism through targeting serine hydroxymethyltranferase (SHMT)1/2 enzymes reduced the infiltration of inflammatory cells in the skin of the imiquimod-induced mouse model of psoriasis. This study investigates the role of serine catabolism in psoriasis, focusing on its influence on keratinocyte proliferation and inflammation. We examined how pharmacological inhibition of SHMT1/2, mediated by a folate-competitive cell-permeable inhibitor Serine Hydroxymethyltransferase INhibitor 1 (SHIN1), affects keratinocyte proliferation and inflammatory signaling pathways in response to psoriasis-associated cytokines IL-22 and IFN-γ, using both in vitro and ex vivo models of the disease. We found that SHIN1 reduced keratinocyte proliferation, particularly under IL-22 stimulation, and restored differentiation in ex vivo psoriasis skin explants by reversing the effects of IL-22. SHIN1 also inhibited IFN-γ-induced expression of pro-inflammatory genes (e.g., CXCL10, CXCL9, CCL5, CCL2, IL-6) and reduced STAT3 activation, with only modest effects on STAT1 and extracellular signal-regulated kinase 1/2 activation. In psoriasis explants, SHIN1 decreased the expression of Ki67, Keratin 16, and pro-inflammatory cytokines including IL-17A, IL-22, and IFN-γ. These findings support the therapeutic potential of SHIN1 as a metabolism-targeted agent for psoriasis and other cytokine-mediated skin disorders, providing a rationale for further exploration of novel treatment strategies.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":" ","pages":""},"PeriodicalIF":7.0,"publicationDate":"2026-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147855944","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":"Synergistic effect of Pladienolide B and cisplatin: enhancing autophagy in hepatoma cells through the AMPK/mTOR/ULK1 pathway.","authors":"Wei Xiao, Lei Yang, Ze Li, Wujie Wang, Zhaojian Liu, Bin Liu, Junchao Qin, Yuliang Li","doi":"10.1038/s41420-026-03144-5","DOIUrl":"https://doi.org/10.1038/s41420-026-03144-5","url":null,"abstract":"<p><p>Alternative splicing (AS) is a key driver of development and a major contributor to species diversity. Accumulating evidence indicates its high activity in various cancers. Here, we identified the spliceosome component SF3B1 as a key regulator of cell fate in hepatocellular carcinoma (HCC), with its expression elevated in HCC tissues/cells versus adjacent non-tumor tissues. Using SF3B1 inhibitor Pladienolide B (Pla B), we found that it suppresses HCC cells' proliferation and induces apoptosis. RNA-Seq revealed Pla B modulates AS events in HCC cells; KEGG analysis indicated it affects the AMPK-mTOR pathway to activate autophagy. In vivo xenograft experiments further demonstrated that the combined treatment of Pla B and cisplatin achieved a more potent inhibitory effect on tumor growth compared to either monotherapy. This combinatorial strategy not only reduced tumor cell proliferation and promoted apoptosis but also enhanced autophagy. Collectively, our findings highlight the potential of combining Pla B with cisplatin as a novel and promising therapeutic approach for the treatment of HCC.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":" ","pages":""},"PeriodicalIF":7.0,"publicationDate":"2026-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147855968","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":"Induction of stress granules alleviates programmed cell death induced by lysosomal damage during NK cell cryopreservation.","authors":"Yang Liu, Xiaolong Liu, Guangyuan Wu, Xin Wang, Kuo Yu, Hailong Wang, Xin Sun, Zhongyao An, Hongrui Xu, Linlin Zhao, Ce Shi, Song Guo Zheng, Mingli Huang, Zhiren Zhang, Zhenkun Wang","doi":"10.1038/s41420-026-03149-0","DOIUrl":"https://doi.org/10.1038/s41420-026-03149-0","url":null,"abstract":"<p><p>Natural killer (NK) cell-based therapies are under assessment for the treatment of various cancers due to their intrinsic ability to distinguish between malignant and healthy cells in an allogeneic context, enabling off-the-shelf manufacturing possibilities. However, cryopreservation reduces both the recovery and function of NK cells, thereby limiting their therapeutic feasibility. In this study, we evaluated three cryoprotectants (CryoStor 10; ZKCELL FM-01; FBS + DMSO) for the cryopreservation of NK cells. Post-thaw viability, ATP levels, and cytotoxicity were assessed and found to have persistent differences between cryopreserved and fresh cells. Transmission electron microscopy, flow cytometry, and Western blot analysis revealed a complex mode of cell death in cryopreserved cells, which could be partially mitigated by adding some death inhibitors. We further investigated the effects of centrifugation on thawed cells, identifying lysosomal stability as a key determinant of cell death. Pretreatment with low-dose LLOMe prior to cryopreservation induced stress granule formation, stabilizing lysosomes and improving cell recovery rates without compromising effector functional capacity. These findings offer new insights for optimizing NK cell cryopreservation and facilitating their clinical application.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":" ","pages":""},"PeriodicalIF":7.0,"publicationDate":"2026-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147833957","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":"RHOV couples EMT-associated plasticity to cytoskeletal execution of invasion and metastasis.","authors":"Qi Wang, Yaru Zhao, Shenghui Huang, Haiyan Fu, Chiara Reina, Alexandra Aicher, Jiajia Tang, Christopher Heeschen","doi":"10.1038/s41420-026-03137-4","DOIUrl":"https://doi.org/10.1038/s41420-026-03137-4","url":null,"abstract":"<p><p>Pancreatic ductal adenocarcinoma (PDAC) is characterized by early invasion and rapid metastatic dissemination, yet the cytoskeletal mechanisms that enable these aggressive behaviors remain incompletely defined. Here, we identify the atypical Rho GTPase RHOV as a critical regulator of invasive progression and metastasis in PDAC. Integrated analyses of independent patient cohorts, patient-derived models, and single-cell transcriptomic datasets revealed that RHOV is selectively overexpressed in malignant epithelial cells, with high RHOV expression correlating with advanced disease stage and poor patient survival. Genetic suppression or deletion of RHOV impaired PDAC cell invasion, migration, clonogenic growth, and context-dependent sphere formation in vitro, while reducing tumor-initiating capacity and metastatic colonization in vivo. Mechanistically, RHOV maintains BRK1-dependent WAVE regulatory complex integrity to sustain lamellipodia formation and invasive motility. Loss of RHOV uncoupled EMT-associated transcriptional programs from cytoskeletal execution of invasion, resulting in compensatory EMT gene expression without restoration of invasive behavior. Re-expression of BRK1 rescued invasion defects following RHOV inhibition. Together, these findings identify RHOV as an executional dependency that enables PDAC invasiveness by linking transcriptional plasticity to actin-based motility.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":" ","pages":""},"PeriodicalIF":7.0,"publicationDate":"2026-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147834017","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":"Spermidine suppresses liver fibrosis by remodeling the communication signal between liver sinusoidal endothelial cells and hepatic stellate cells.","authors":"Cheng Zeng, Jiao Liu, Zhiqiang Jin, Shan Zhong, Rong Wu, Haoyue Luo, Tao Zeng, Yang Yang, Zhi Zhou","doi":"10.1038/s41420-026-03129-4","DOIUrl":"https://doi.org/10.1038/s41420-026-03129-4","url":null,"abstract":"<p><p>Hepatic fibrosis is a pivotal stage in which chronic liver disease progresses from reversible injury to decompensation. Liver sinusoidal endothelial cells (LSECs) play a regulatory role in hepatic stellate cells (HSCs) activation through paracrine signaling; therefore, maintaining the physiological phenotype of LSECs is critical for antifibrotic intervention. Spermidine (SPD) has been recognized for its antifibrotic properties; however, its impact on LSECs' function and the underlying mechanism remains largely unknown. In this study, analysis of NHANES data revealed an inverse association between dietary SPD intake and fibrosis risk. Consistently, in vivo and in vitro models demonstrated that SPD significantly ameliorated LSECs dysfunction and attenuated fibrosis progression. Through an integrative analysis incorporating proteomics, public single-cell datasets, and machine-learning prioritization, we identified LSECs-derived biglycan (BGN) as a principal target of SPD; notably, BGN overexpression diminished the capacity of SPD to restore LSECs function and facilitated HSCs activation. Mechanistically, SPD activated NRF2 to increase UBE2G2 expression, thereby enhancing UBE2G2-dependent ubiquitination and degradation of BGN. UBE2G2 knockdown reversed SPD-induced BGN downregulation, subsequently exacerbating LSECs capillarization and enhancing HSCs activation. Furthermore, Bgn overexpression in the CCl₄-induced mouse model markedly attenuated the ability of SPD to improve LSECs dysfunction and its antifibrotic efficacy. In conclusion, our findings uncover a novel mechanism whereby SPD ameliorates LSECs dysfunction and suppresses fibrosis progression by modulating LSECs-derived BGN, suggesting a new therapeutic strategy for liver fibrosis.Schematic working model of the study. SPD promotes UBE2G2-dependent ubiquitination and proteasomal degradation of BGN, thereby attenuating ERK/p38 phosphorylation, ameliorating LSECs dysfunction, and suppressing HSCs activation.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":" ","pages":""},"PeriodicalIF":7.0,"publicationDate":"2026-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147834117","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":"FBXL6 promotes bladder cancer progression by stabilizing ENO1 through K63-linked ubiquitination.","authors":"Ruoyu Huang, Jingtian Yu, Renran Bai, Wenyu Jiang, Fenfang Zhou, Tongzu Liu, Xinghuan Wang","doi":"10.1038/s41420-026-03130-x","DOIUrl":"https://doi.org/10.1038/s41420-026-03130-x","url":null,"abstract":"<p><p>The role of ubiquitin in post-translational modifications is important for tumor progression, but how these mechanisms regulate bladder cancer (BLCA) is not completely known. The study demonstrated that FBXL6, a member of the F-box protein family, could drive oncogenesis in BLCA, as shown by integrative bioinformatic analysis and clinical sample validation. Experiments demonstrated that FBXL6 speeds up the in vitro growth and migration of BLCA cells and contributes to tumor development and metastasis in vivo. Mechanistically, transcriptomic and metabolic studies indicate that FBXL6 regulates the glycolytic pathway. Although FBXL6 knockdown has minimal impact on the mRNA levels of the key glycolytic enzyme ENO1, FBXL6 knockdown does alter ENO1 protein levels, suggesting post-translational regulation. Co-immunoprecipitation and GST pull-down assays validated the interaction between FBXL6 and ENO1, confirming that the LRR domain of FBXL6 and the C-terminal region of ENO1 are essential for their binding. Additionally, ubiquitination assays indicated that FBXL6 promotes K63-linked polyubiquitination of ENO1, which stabilizes it. Bringing back ENO1 expression partially offset the consequences of FBXL6 knockdown on proliferation and migration. In summary, our findings propose a new model where FBXL6 promotes BLCA progression by stabilizing ENO1 through K63 linkage, emphasizing its potential as a target for BLCA therapy.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":" ","pages":""},"PeriodicalIF":7.0,"publicationDate":"2026-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147833833","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":"miR-205a mediated suppression of CDH11 disrupts Wnt/β-catenin signaling and impairs chondrocyte differentiation.","authors":"Kai Liu, Buyun Chen, Junhong Hou, Yuanliang Li, Lihong Ning, Shaochuan Li, Ying Li, Aoyun Li, Quazi T H Shubhra, Hui Zhang","doi":"10.1038/s41420-026-03146-3","DOIUrl":"https://doi.org/10.1038/s41420-026-03146-3","url":null,"abstract":"<p><p>The precise regulation of chondrocyte differentiation is critical for endochondral ossification, and its disruption underlies a spectrum of skeletal diseases. While the Wnt/β-catenin signaling pathway is a well-established master regulator of skeletal development, its precise regulation during chondrogenesis remains incompletely understood. Here, we identify a novel regulatory axis centered on microRNA-205a and its target, the adhesion molecule Cadherin-11 (CDH11), in avian embryonic models. We demonstrate that CDH11 functions as a positive regulator of chondrocyte differentiation by promoting Wnt/β-catenin signaling. Conversely, miR-205a acts as a potent endogenous inhibitor of this process. Through dual-luciferase reporter assays, we confirm that miR-205a directly binds to the 3'UTR of CDH11 mRNA. Functional studies revealed that miR-205a overexpression suppresses chondrogenesis by downregulating CDH11, thereby inhibiting the Wnt/β-catenin pathway and key chondrogenic markers like Runx2 and BMP2. Silencing miR-205a or overexpressing CDH11 produced the opposite effect, promoting the differentiation program. Critically, rescue experiments using a Wnt/β-catenin pathway agonist substantiated that miR-205a exerts its inhibitory effects primarily through modulating this pathway. Our findings delineate a conserved miR-205a/CDH11/Wnt-β-catenin regulatory circuit that is essential for chondrocyte differentiation, offering fundamental new insights into the molecular etiology of cartilage development and its associated disorders.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":" ","pages":""},"PeriodicalIF":7.0,"publicationDate":"2026-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147833972","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":"Correction: A high-fructose diet leads to osteoporosis by suppressing the expression of Thrb and facilitating the accumulation of cholesterol.","authors":"Jun Chen, Xinquan Jiang","doi":"10.1038/s41420-026-03126-7","DOIUrl":"https://doi.org/10.1038/s41420-026-03126-7","url":null,"abstract":"","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":"12 1","pages":""},"PeriodicalIF":7.0,"publicationDate":"2026-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13144342/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147834182","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":"Correction: NCOA7 inhibits renal cancer progression by inducing autophagy and lipid metabolism through V-ATPase interaction.","authors":"Jianjun Wang, Huiwen Luo, Qingliu He, Honggang Shao, Xianfu Cai, Yuan Cao, Yaodong Wang, Decai Wang","doi":"10.1038/s41420-026-02952-z","DOIUrl":"https://doi.org/10.1038/s41420-026-02952-z","url":null,"abstract":"","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":"12 1","pages":""},"PeriodicalIF":7.0,"publicationDate":"2026-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13144378/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147834192","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":"YWHAZ-mediated metabolic reprogramming via HIF1A/LDHA signaling promotes pulmonary arterial remodelling.","authors":"Zhong-Yuan Meng, Chuang-Hong Lu, Juan Liao, Sen-Hu Tang, Jing Li, Xiao-Li Ma, Yue Qin, Chao-Yong Zhang, Yao-Shi Hu, De-Xin Chen, Xing Chen, Yan Deng, Feng Huang, Zhi-Yu Zeng","doi":"10.1038/s41420-026-03121-y","DOIUrl":"https://doi.org/10.1038/s41420-026-03121-y","url":null,"abstract":"<p><p>Hypoxia-related pulmonary arterial hypertension (PAH) remains poorly managed by current therapies. Metabolic dysregulation, particularly glycolysis, plays a key role in PAH pathogenesis. This study investigated YWHAZ's role in PAH using hypoxia-induced pulmonary arterial endothelial cells (PAECs) and a hypoxia/SU5416-induced PAH rat model. Silencing YWHAZ inhibited PAEC proliferation, migration, and glycolysis, while improving right ventricular function and reducing pulmonary vascular remodeling. Mechanistically, YWHAZ stabilized HIF-1α, which transcriptionally activated LDHA, a critical glycolytic enzyme. HIF-1α agonist treatment reversed YWHAZ silencing effects, confirming the YWHAZ/HIF-1α/LDHA axis. These findings highlight YWHAZ as a potential therapeutic target for metabolic intervention in PAH.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":" ","pages":""},"PeriodicalIF":7.0,"publicationDate":"2026-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147834064","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}