Cell Death & Disease最新文献

{"title":"Retraction Note: Circular RNA profiling reveals an abundant circLMO7 that regulates myoblasts differentiation and survival by sponging miR-378a-3p.","authors":"Xuefeng Wei, Hui Li, Jiameng Yang, Dan Hao, Dong Dong, Yongzhen Huang, Xianyong Lan, Martin Plath, Chuzhao Lei, Fengpeng Lin, Yueyu Bai, Hong Chen","doi":"10.1038/s41419-026-09250-7","DOIUrl":"10.1038/s41419-026-09250-7","url":null,"abstract":"","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"17 1","pages":""},"PeriodicalIF":12.2,"publicationDate":"2026-09-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13550560/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148905234","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The skin-specific long non-coding RNA TEDAR orchestrates late epidermal differentiation via an ERK-KLF4 cytoplasmic regulatory axis.","authors":"Kunal Das Mahapatra, Özge Arslan, Longlong Luo, Evelyn Kelemen, Sreeram Peringattu Kalarikkal, Lorenzo Pasquali, Christian Ziegler, Johannes Graf, Nicole Hemmer, Rachael Sugars, Markus Kretz, Eniko Sonkoly, Andor Pivarcsi","doi":"10.1038/s41419-026-09192-0","DOIUrl":"10.1038/s41419-026-09192-0","url":null,"abstract":"<p><p>The formation of a functional skin barrier depends on terminal keratinocyte differentiation, yet the contribution of long non-coding RNAs to this process remains incompletely understood. Here, using transcriptome analysis of more than 15,000 RNA-seq samples across 54 human tissues, we identify TEDAR (Terminal Epidermal Differentiation-Associated RNA), a highly skin-enriched lncRNA. Single-molecule RNA in situ hybridization revealed that TEDAR is confined to the uppermost granular layer of the epidermis, representing an exceptionally spatially restricted expression pattern. Functional studies demonstrated that CRISPR-mediated activation of TEDAR promotes keratinocyte differentiation even in the absence of external cues, while its depletion impaired late epidermal differentiation. In three-dimensional skin equivalents, TEDAR depletion severely compromises stratum corneum formation, highlighting its importance for proper epidermal barrier assembly. Mechanistically, TEDAR associates with ERK1/2-containing complexes and restrains ERK phosphorylation, thereby facilitating the nuclear accumulation of KLF4, a key regulator of epidermal differentiation. KLF4 depletion attenuated TEDAR-induced expression of several late differentiation genes, supporting a functional TEDAR-ERK-KLF4 axis. Clinically, TEDAR expression was reduced in cutaneous squamous cell carcinoma (cSCC) and chronic inflammatory skin diseases, including psoriasis and atopic dermatitis. Moreover, IL-22 suppressed TEDAR via STAT3 signalling in epidermal models. These findings identify TEDAR as an important regulator of terminal epidermal differentiation and suggest that its suppression may contribute to disturbed differentiation in inflammatory and neoplastic skin diseases.</p>","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"17 1","pages":""},"PeriodicalIF":12.2,"publicationDate":"2026-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13550425/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148905209","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeting FEN1 disrupts EIF4A3-mediated MUC1-C autoregulation: a novel strategy to suppress lung adenocarcinoma progression.","authors":"Min Wu, Benmeng Wu, Xuebing Yan, Zirui Wang, Chunyan Mei, Xiaoshan Huang, Guorui Li, Ji Pang, Lin Yu, Jingjing Liu","doi":"10.1038/s41419-026-09260-5","DOIUrl":"10.1038/s41419-026-09260-5","url":null,"abstract":"<p><p>Flap endonuclease 1 (FEN1), a key enzyme in DNA metabolism, exhibits oncogenic properties in various cancers. However, its functional role and underlying mechanisms in lung adenocarcinoma (LUAD) progression and tumor immunity remain poorly defined. Here, we demonstrate that FEN1 is significantly upregulated in LUAD tissues and serves as an independent prognostic factor for poor survival. Genetic depletion of FEN1 suppressed LUAD cell proliferation by inducing G0/G1 cell cycle arrest and cellular senescence, while significantly impairing migration and invasion capabilities. Mechanistically, integrated proteomic and molecular analyses revealed that FEN1 knockdown disrupts the carboxyl-terminal subunit of mucin 1 (MUC1-C)/PI3K/AKT autoregulatory loop, a critical driver of oncogenic signaling. Furthermore, FEN1 downregulation inhibited the MUC1-C/p65/ programmed death-ligand 1 (PD-L1) signaling axis, thereby alleviating tumor-mediated immunosuppression. This was evidenced by enhanced antitumor immunity, characterized by the local expansion of CD4⁺ T cells and restored effector function of CD8⁺ T cells, both in vitro and in vivo. Mechanistically, independent of its nuclease activity, FEN1 interacts with the N-terminus of eukaryotic translation initiation factor 4A3 (EIF4A3) to facilitate its binding to MUC1-C mRNA. Specifically, FEN1 is required for EIF4A3-mediated maintenance of both the transcript stability and translation efficiency of MUC1-C. Clinically, FEN1, MUC1-C, and PD-L1 are coordinately upregulated in LUAD tissues, and their co-expression predicts poor patient survival irrespective of EGFR mutation status. Our findings establish the FEN1/EIF4A3/MUC1-C axis as a novel mechanism driving LUAD progression by concurrently regulating intrinsic malignancy and extrinsic immune evasion, presenting FEN1 targeting as a promising dual-hit therapeutic strategy.</p>","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"17 1","pages":""},"PeriodicalIF":12.2,"publicationDate":"2026-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13675245/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149206597","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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: Model organisms in POLG-related disorders: insights from yeast to multicellular systems.","authors":"Raquel Brañas Casas, Giovanni Risato, Alessandro Zuppardo, Carlo Viscomi, Francesco Argenton, Mara Doimo, Nicola Facchinello, Natascia Tiso","doi":"10.1038/s41419-026-09022-3","DOIUrl":"10.1038/s41419-026-09022-3","url":null,"abstract":"","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"17 1","pages":""},"PeriodicalIF":12.2,"publicationDate":"2026-08-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13530166/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148863622","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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: ANP32E drives lung adenocarcinoma progression via GSK3β-mediated glycolytic reprogramming.","authors":"Zhongliang Wang, Qianxia Li, Zeguang Ye, Xi Wu, Can Fang, Wenyang Jiang, Min Zhu","doi":"10.1038/s41419-026-09041-0","DOIUrl":"10.1038/s41419-026-09041-0","url":null,"abstract":"","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"17 1","pages":""},"PeriodicalIF":12.2,"publicationDate":"2026-08-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13530245/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148863624","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Exendin-4 improves neurodevelopmental outcome after neonatal germinal matrix hemorrhage.","authors":"Andrea Jonsdotter, Anna-Lena Leverin, Pernilla Svedin, Michelle Lindström, Kerstin Ebefors, Ylva Carlsson, Henrik Hagberg, Eridan Rocha-Ferreira","doi":"10.1038/s41419-026-09189-9","DOIUrl":"https://doi.org/10.1038/s41419-026-09189-9","url":null,"abstract":"<p><p>Germinal matrix hemorrhage (GMH) is a common complication in premature infants and is associated with a high risk of neurodevelopmental impairment and mortality. Currently, there are no specific neuroprotective treatments available. Exendin-4 is a drug used for the treatment of type 2 diabetes mellitus, and it has shown neuroprotective effects in several neurological disorders including Alzheimer's and Parkinson's disease. In this study, we used the preterm postnatal day 5 rat model of GMH to evaluate whether exendin-4 exerts neuroprotective effects in this setting. Our results show that in the acute phase, exendin-4 reduced microglial activation, caspase-3 activation, p53 expression, AIF-associated cell death, MMP-9 expression, and neutrophil infiltration into the hemorrhage site. Exendin-4 treatment improved neurodevelopmental outcomes in both negative geotaxis and eye-opening latency when compared to saline-treated GMH controls, and conferred gray and white matter protection as early as 48 h after injury, with persistent neuroprotection observed at 5, 11, and 35 days after GMH. Exendin-4-treated animals also showed significant recovery of motor function in the rotarod test. In summary, this study demonstrates that exendin-4 reduces brain injury in a rat model of GMH in both the short and long term and is associated with improved neurological outcome.</p>","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"17 1","pages":""},"PeriodicalIF":12.2,"publicationDate":"2026-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13490559/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148788809","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Loss of CD44 re-educates pancreatic cancer-associated fibroblasts modulating their fibrotic and immunosuppressive functions.","authors":"Sven Máté Treffert, Yvonne Madeleine Heneka, Julie Martin, Alessandra Gargano, Larissa Launhardt, Özlem Akilli, Eliana Stanganello, Geoffroy Andrieux, Dominique Hoch, Steffen Joachim Sonnentag, Lisa-Marie Mehner, Leonel Munoz-Sagredo, Michelle Christ, Véronique Orian-Rousseau","doi":"10.1038/s41419-026-09155-5","DOIUrl":"10.1038/s41419-026-09155-5","url":null,"abstract":"<p><p>Pancreatic tumors are characterized by a prominent desmoplastic stroma that can account for up to 90% of the tumor. Given the marked upregulation of CD44, a family of transmembrane glycoproteins, in pancreatic cancer-associated fibroblasts (CAFs), we investigated its role in regulating myofibroblastic and inflammatory CAF phenotypes. Conditional deletion of Cd44 in fibroblastic cells in Cd44^fl/fl;PdgfrβCreER^T2 mice significantly reduced tumor growth and was associated with a significant reduction in intratumoral regulatory T cells (T_reg). Consistently, in human CAFs CRISPR/Cas9-edited to delete CD44, the fibroblasts' morphology changed drastically: CAFs lost their elongated phenotype and adopted a round shape, reflecting their inactivation. This was accompanied by a significant downregulation of activation markers, unresponsiveness to exogenous stimuli, and reduced contractile activity. Furthermore, CD44 ablation decreased extracellular matrix production and altered the immunomodulatory cytokine secretion, highlighting its role in both fibrosis and immune regulation. Finally, CD44-deficient CAFs exhibited a reduced capacity to suppress anti-tumor immune responses by failing to induce immunosuppressive programs in dendritic cells (DCs) and by increasing cytotoxic T cell (CTL)-mediated tumor cell killing. Collectively, we identify CD44 as a regulator of CAF activation and immunosuppressive function, linking stromal remodeling to immune evasion in pancreatic cancer and supporting CD44 as a potential therapeutic strategy to reprogram the tumor stroma and enhance anti-tumor immunity.</p>","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"17 1","pages":""},"PeriodicalIF":12.2,"publicationDate":"2026-08-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13477481/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148758836","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mesenchymal stromal cells immunosuppress osteoarthritis synovial fluid modulated monocytes via IL-6 and CCL2.","authors":"Mozhgan Rasti, Aida Feiz Barazandeh, Shahrzad Nouri, Kevin P Robb, Rachel Low, Oreoluwa Kolade, Kevin Fan, Rajiv Gandhi, Sowmya Viswanathan","doi":"10.1038/s41419-026-09194-y","DOIUrl":"10.1038/s41419-026-09194-y","url":null,"abstract":"<p><p>Mesenchymal stromal cell (MSC) interactions with monocytes/macrophages are central to their therapeutic effects in knee osteoarthritis (KOA); however, mechanisms of these interactions are not fully understood. We hypothesize that MSC soluble factors, particularly interleukin-6 (IL-6) and C-C motif chemokine ligand (CCL2) modulate monocytes in KOA environment. Using healthy donor CD14⁺ monocytes exposed to KOA synovial fluid (SF) in the presence or absence of marrow-derived MSC(M) directly or conditioned medium (CM), we evaluated cell surface markers and signaling via signal transducer and activator of transcription (STAT3), nuclear factor kappa-light-chain-enhancer of activated B (NF-κB) and c-Jun Terminal Kinase (JNK); functional responses were measured by secretion of tumor necrosis factor (TNF) and IL-1, and by phagocytosis of pHrodo Red E-coli. CD14⁺ monocytes demonstrated a mixed phenotype in KOA SF with increased CD163, CD206, and unchanged HLA-DR, CD86 marker expression. This was accompanied by activated STAT3, JNK, and NF-κB signaling. TNF and IL-1 secreted levels were unchanged, but phagocytosis was impaired, indicative of a net dysfunctional repair phenotype and functionality. CD14⁺ monocytes in KOA SF were hyporesponsive to additional lipopolysaccharide re-challenge, based on TNF and IL-1 secretion. Addition of MSC(M) to KOA SF programmed CD14⁺ monocytes resolved the dysfunctional phenotype and functionality, with significant increases in CD163, CD206; significant reductions in HLA-DR and CD86 expression; this was accompanied by significantly increased activated STAT3 and decreased activated JNK and NF-κB. TNF and IL-1 secretion were also significantly reduced, and phagocytic capacity restored. Blocking IL-6, or to a lesser extent, CCL2, partially abrogated MSC(M) soluble factor effects. MSC(M) experienced apoptosis in KOA SF; however, apoptotic bodies did not fully recapitulate MSC(M) soluble factor effects. IL-6, CCL2, other soluble factors and apoptotic bodies from MSC(M) secretome mitigate the dysfunctional effects of KOA SF on CD14⁺ monocytes resulting in immunosuppressed phenotype and functionality.</p>","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"17 1","pages":""},"PeriodicalIF":12.2,"publicationDate":"2026-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13669379/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149179621","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"SNAI1 ablation alters integrin-mediated adhesion and endocytic fate.","authors":"Chrysoula Tsirigoti, Mohamad Moustafa Ali, Anita Morén, Staffan Johansson, Michael J Munson, Carl-Henrik Heldin, Aristidis Moustakas, Dorival Mendes Rodrigues-Junior","doi":"10.1038/s41419-026-09179-x","DOIUrl":"10.1038/s41419-026-09179-x","url":null,"abstract":"<p><p>Transcription factor SNAI1 guides plasticity and invasiveness in cancer. Using a complete SNAI1 knockout in mesenchymal, triple-negative breast cancer cells, unbiased genome-wide transcriptomic analysis revealed a marked under-expression of integrin-based adhesion and endocytic components. Utilizing this knockout cell model, complementary breast cancer cell models and functional screening of multiple differentially expressed genes, we found that the pioneering transcription factor FOXA1, whose expression is repressed by SNAI1, associates with several key mediators of the cellular phenotype. FOXA1 represses the small GTPase ARF6 and its exchange factor PSD4. In addition, some of the integrin and matrix metalloproteinase genes are regulated by the transcriptional FOXA1 signal. Accordingly, SNAI1 knockout cells presented poor adhesion to collagen type I or fibronectin, formed defective invadopodia and focal adhesions with weakened FAK/SRC signaling. SNAI1 knockout cells performed ineffective receptor-mediated internalization, including nanoparticle and extracellular vesicle (EV) uptake, exhibited reduced lysosomal content, lacked multivesicular bodies enriched in intraluminal vesicles and showed decreased EV secretion. Gain-of-function experiments demonstrated that SNAI1 has an impact on the PSD4/ARF6 signaling module, using FOXA1 as an intermediate factor to regulate EV release by tumor cells. We propose that the SNAI1-FOXA1 transcriptional mechanism operates at the level of membrane and vesicular trafficking control, which interlinks cell plasticity, adhesion and invasiveness through the extracellular environment, with the associated process of EV secretion.</p>","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"17 1","pages":""},"PeriodicalIF":12.2,"publicationDate":"2026-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13470233/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148720499","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Fructose induces PERK-dependent ER stress and mitochondrial dysfunction via nucleotide depletion in clear cell renal cell carcinoma.","authors":"Na Li, Yanhong Ding, Bowen Yu, Yongqiang Wang, Tongbin Gao, Huiyong Yin, Zhenhua Li, Shuzhen Liu, Guohua Yu, Ningning Wang","doi":"10.1038/s41419-026-09157-3","DOIUrl":"10.1038/s41419-026-09157-3","url":null,"abstract":"<p><p>Clear cell renal cell carcinoma (ccRCC) exhibits a paradoxical fructose metabolism signature characterized by upregulation of the fructose transporter GLUT5 alongside downregulation of the catabolic enzymes (ketohexokinase, aldolase B, and triokinase), a pattern associated with poor prognosis. Functionally, unlike the pro-survival effect of fructose under glucose deprivation, in the presence of glucose, fructose co-treatment suppresses ccRCC cell proliferation, and induces profound mitochondrial dysfunction, including impaired oxidative phosphorylation, loss of membrane potential, excessive mitochondrial superoxide production, reduced mtDNA copy number, and downregulation of mitochondria-encoded electron transport chain subunits (notably ND2 and ND4 of complex I). Mechanistically, co-treatment with glucose and fructose creates a metabolic trap resulting in fructose-1-phosphate accumulation and ATP depletion. This energy crisis drives profound depletion of purine and pyrimidine nucleotide pools, which selectively triggers the PERK-eIF2S1-ATF4-CHOP axis of the integrated stress response, thereby mediating mitochondrial impairment and ultimately sensitizing ccRCC cells to intrinsic apoptosis via BID cleavage and caspase-3 activation under nutrient stress. Pharmacological treatment with the chemical chaperone 4-phenylbutyric acid (4-PBA) or nucleoside supplementation reverses mitochondrial dysfunction and fructose-induced cytotoxicity. The tumor-suppressive effect of fructose is validated in patient-derived organoids and xenograft mouse models, where fructose administration significantly attenuates tumor growth via ER stress. These findings reveal fructose-driven nucleotide depletion and PERK-dependent ER stress leading to mitochondrial dysfunction, which underlies the tumor-suppressive toxicity of fructose and exposes a targetable metabolic vulnerability in ccRCC.</p>","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"17 1","pages":""},"PeriodicalIF":12.2,"publicationDate":"2026-08-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13530255/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148863645","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}