Cell Death & Disease最新文献

{"title":"Retraction Note: Modulation of aberrant CDK5 signaling rescues impaired neurogenesis in models of Alzheimer's disease.","authors":"L Crews, C Patrick, A Adame, E Rockenstein, E Masliah","doi":"10.1038/s41419-026-09413-6","DOIUrl":"https://doi.org/10.1038/s41419-026-09413-6","url":null,"abstract":"","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"17 1","pages":""},"PeriodicalIF":12.2,"publicationDate":"2026-11-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149370020","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":"Physiological APP processing is required for synaptic plasticity and cognition.","authors":"Lara Kilian, Verena Bengelsdorff, Jennifer Just, Sebastian Stork, Christos Galanis, Marija Banicevic, Irmgard Amrein, Michaela Back, Tassilo Jungenitz, Meike Fellenz, Jakob von Engelhardt, Thomas Deller, David P Wolfer, Andreas Vlachos, Martin Korte, Ulrike C Müller","doi":"10.1038/s41419-026-09378-6","DOIUrl":"10.1038/s41419-026-09378-6","url":null,"abstract":"<p><p>While the accumulation of Aβ peptides, derived by proteolytic cleavage from the amyloid precursor protein APP, constitutes a hallmark of Alzheimer's disease, the question of whether endogenous, physiological APP processing serves an essential role for normal brain function(s) has remained elusive. Here, we modified the mouse APP locus to delete the endogenous α- and β-secretase sites (APP residues S592-G621) while preserving the transmembrane topology and the APP C-terminus. These novel knockin mice (termed APPΔS622) lack APPsα, APPβ, and Aβ production and show only minimal soluble APPs shedding. These APPΔS622 mice provide a unique model to distinguish between functions mediated by unprocessed cell surface APP involved in synaptic adhesion or by proteolytic fragments. Strikingly, APPΔS622 mice exhibit pronounced impairments in both long-term potentiation (LTP) and homeostatic forms of synaptic plasticity. Extracellular field recordings revealed significant deficits in hippocampal LTP, associated with a reduced density of mature spines and reduced spine head size. LTP deficits could be restored by APPsα application, suggesting a requirement for non-amyloidogenic APP processing for LTP. In addition, APPΔS622 mice lacking endogenous Aβ displayed a lack of homeostatic synaptic scaling in response to network impairment that could be specifically rescued by exogenous Aβ. Importantly, these deficits in different forms of synaptic plasticity also led to impairments in cognitive behavior. In summary, our findings reveal an essential role of physiological APP processing products to differentially regulate complementary forms of synaptic plasticity that are critical for network stability, normal brain function and cognition.</p>","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"17 1","pages":""},"PeriodicalIF":12.2,"publicationDate":"2026-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13737196/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149332681","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":"Retraction Note: Upregulated long non-coding RNA AGAP2-AS1 represses LATS2 and KLF2 expression through interacting with EZH2 and LSD1 in non-small-cell lung cancer cells.","authors":"W Li, M Sun, C Zang, P Ma, J He, M Zhang, Z Huang, Y Ding, Y Shu","doi":"10.1038/s41419-026-09398-2","DOIUrl":"10.1038/s41419-026-09398-2","url":null,"abstract":"","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"17 1","pages":""},"PeriodicalIF":12.2,"publicationDate":"2026-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13736914/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149332683","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":"XIAP induces inflammation and promotes colorectal cancer progression.","authors":"Lars M Schiffmann, Mila Daoud, Claudia Maria Wunderlich, Fabian Schorn, Johanna Stachelscheid, Pia Nora Broxtermann, Marie-Christine Albert, M Siebenbürger, Heike Göbel, Ulrike Göbel, Ali T Abdallah, J Paul Werthenbach, Jens Michael Seeger, Naita M Wirsik, Karl Knipper, Su Ir Lyu, Thomas Schmidt, Nikolai Schleußner, Uraz Yasar, Christian Goddemeier, Stephanie T Jünger, Hans A Schlößer, Georg Dieplinger, Thomas Zander, Hakan Alakus, Hans F Fuchs, Florian Gebauer, Christiane J Bruns, Domagoj Vucic, Alexander Quaas, Melanie Fritsch, Frank Thomas Wunderlich, Hamid Kashkar","doi":"10.1038/s41419-026-09391-9","DOIUrl":"10.1038/s41419-026-09391-9","url":null,"abstract":"<p><p>Colorectal cancer (CRC) is one of the most diagnosed malignancies worldwide, with chronic inflammation playing a critical role in its pathogenesis and progression. Surgery represents the primary treatment option, though some patients suffer from relapse, leading to considerable morbidity and mortality. A better molecular understanding of CRC pathogenesis is therefore essential for identifying patients at increased risk of recurrence and improving clinical management. Here we identified the X-linked inhibitor of apoptosis protein (XIAP) as an independent predictor of overall survival in primary resected CRC patients. To model CRC patients with low versus high XIAP expression, we established conditional mouse lines for intestinal epithelial cell (IECs)-specific Xiap knock-out and XIAP knock-in, and employed a colitis-associated murine model for CRC. We found that XIAP promotes inflammatory signalling and exacerbates colitis-driven colorectal tumorigenesis by shaping a distinct tumor inflammatory microenvironment characterized by increased immune-cell infiltration, including neutrophils, and enhanced vascularisation. The pro-inflammatory role of XIAP was further validated in CRC patient-derived organoids and human CRC tumor specimens. Collectively, our findings identify XIAP as a potential biomarker of CRC-associated inflammation and a candidate marker for identifying patients at increased risk of disease recurrence. Moreover, these results provide a rationale for exploring XIAP-targeting strategies as a potential component of multimodal therapeutic approaches for CRC.</p>","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"17 1","pages":""},"PeriodicalIF":12.2,"publicationDate":"2026-11-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13728099/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149318428","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":"Role of the ACTH-SF1/NR5A1-NRF2 axis in glucocorticoid-induced adrenocortical cell death through mitochondrial ROS accumulation.","authors":"Naohiro Uchida, Namiko Kawamura, Hironobu Umakoshi, Maki Yokomoto-Umakoshi, Tazuru Fukumoto, Norifusa Iwahashi, Masamichi Fujita, Aya Fujimoto, Kaede Saito, Yuta Hiraike, Fumiya Takahashi, Takashi Baba, Masahide Seki, Yutaka Suzuki, Yoshihiro Ogawa","doi":"10.1038/s41419-026-09306-8","DOIUrl":"10.1038/s41419-026-09306-8","url":null,"abstract":"<p><p>Exogenous glucocorticoids are widely used to treat inflammatory and autoimmune diseases, yet the prolonged administration often leads to adrenocortical atrophy and subsequent adrenal insufficiency. However, the molecular mechanisms underlying glucocorticoid-induced adrenocortical atrophy remain incompletely understood. Here, we show that adrenocortical alterations in dexamethasone (DEX)-treated mice are similar to those in human adrenocortical tissues adjacent to cortisol-producing adenoma. During DEX treatment, marked cell death occurs, being restricted to the adrenocortical zona fasciculata (ZF), as a result of reactive oxygen species (ROS)-mediated mitochondrial dysfunction; the pathological changes are all attenuated by co-administration of adrenocorticotropic hormone (ACTH). In DEX-treated mice, ACTH deficiency impairs nuclear factor E2-related factor 2 (NRF2)-dependent redox homeostasis in ZF cells. Activation of the cAMP-PKA signaling pathway, a downstream signaling of ACTH stimulation, increases gene expression of steroidogenic factor 1 (SF1; NR5A1) in cultured adrenocortical cells in vitro, where it binds directly to the Nrf2 promoter and enhances its transcription, thereby promoting antioxidant gene expression to maintain redox homeostasis. This study highlights the role of the ACTH-SF1-NRF2 axis in glucocorticoid-induced adrenocortical cell death through mitochondrial ROS accumulation, thereby providing a clue to a new therapeutic strategy to prevent or treat secondary adrenal insufficiency during glucocorticoid excess.</p>","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"17 1","pages":""},"PeriodicalIF":12.2,"publicationDate":"2026-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13720010/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149295022","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":"Autophagy and intratumoral bacteria abundance influence the prognosis of patients with pancreatic carcinoma.","authors":"Yifan Zhang, Toohina L Gobin, Zhenhua Huang, Bingwen Miao, Roma Kurilov, Haitao Sun, Christine Tjaden, Ulrike Heger, Thilo Hackert, Ulf Hinz, Michael Schaefer, Frank Bergmann, Christoph Springfeld, Sadaf S Mughal, Benedikt Brors, Patrick Schaal, Bachar Cheaib, Danilo Licastro, Valerio Iebba, Franco Fortunato","doi":"10.1038/s41419-026-09256-1","DOIUrl":"10.1038/s41419-026-09256-1","url":null,"abstract":"<p><p>The biological and clinical significance of the intratumoral microbiota in pancreatic ductal adenocarcinoma (PDAC) remains poorly defined. Using oncogenic Kras-driven mouse models of pancreatic tumorigenesis and human pancreatic tissue from patients with non-metastatic PDAC treated with neoadjuvant (n = 62) or adjuvant therapy (n = 101), along with samples from intraductal papillary mucinous neoplasms (IPMN, n = 24), chronic pancreatitis (CP, n = 33), and healthy donors (n = 9), we determined tissue lipopolysaccharide (LPS), 16S rRNA sequencing, high-resolution quantitative multiplex immunofluorescence of autophagy markers (LAMP2, LC3B) and LPS, 16S rRNA fluorescence in situ hybridization (FISH) staining, and TLR4 signaling. In KrasCre mice, we identified significant bacterial accumulation in the pancreas, indicated by elevated LPS, increased FISH signals, enhanced TLR4 signaling, and activation of autophagy. Administration of exogenous LPS further amplified autophagy and TLR4 signaling, supporting a mechanistic link between microbial sensing and autophagy. In human tissue, both adjuvant and neoadjuvant PDAC samples showed significantly increased bacterial alpha- and beta diversity compared with controls, while CP showed a similar enrichment pattern that IPMN lacks; the underlying microbial diversity differs fundamentally across these conditions. Increased LPS levels, along with elevated autophagy markers and abundant FISH-positive bacteria, support the presence of intratumoral bacteria. Across four independent transcriptomic datasets, PDAC samples showed elevated expression of bacteria-associated pathways (including TLR4) and autophagy-related genes. Clinically, higher autophagy-associated LAMP2-LC3B colocalization and increased densities of FISH-positive cells were independently associated with prolonged survival in both adjuvant and neoadjuvant or combined PDAC patients. Collectively, these findings link intratumoral microbial enrichment to increased autophagy-associated signaling and improved patient outcomes, suggesting that microbial signals within the tumor microenvironment were associated with favorable survival.</p>","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"17 1","pages":""},"PeriodicalIF":12.2,"publicationDate":"2026-10-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13720179/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149295042","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":"Retraction Note: Histone acetyltransferase PCAF accelerates apoptosis by repressing a GLI1/BCL2/BAX axis in hepatocellular carcinoma.","authors":"X Gai, K Tu, C Li, Z Lu, L R Roberts, X Zheng","doi":"10.1038/s41419-026-09338-0","DOIUrl":"10.1038/s41419-026-09338-0","url":null,"abstract":"","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"17 1","pages":""},"PeriodicalIF":12.2,"publicationDate":"2026-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13649731/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149135155","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":"Apoptotic cell overload drives multinucleated giant cell formation after neoadjuvant chemotherapy in colorectal cancer: molecular mechanisms and tumor-suppressive effects.","authors":"Jiaxin Xue, Zhiwei Wang, Xiaoliang Zhang, Sen Xu, Shuang Wu, Xiaoyue Sun, Meiqi Li, Xueyan Wu, Zhangming Chen, Ming Lu","doi":"10.1038/s41419-026-09320-w","DOIUrl":"10.1038/s41419-026-09320-w","url":null,"abstract":"<p><p>Colorectal cancer is a common digestive malignancy. Neoadjuvant chemotherapy (NAC) can downstage tumors and increase R0 resection rates. In colorectal cancer specimens with favorable pathological regression after NAC, we observed CD68⁺ multinucleated giant cells (MGCs) preferentially localized in apoptotic cell-rich areas, whereas they were rarely detected in non-NAC specimens. However, the mechanisms driving MGC formation and their functional significance remain unclear. We established an in vitro apoptotic cell-macrophage co-culture system to assess how apoptotic cell burden and efferocytosis regulate macrophage fusion. The TREM2/TYROBP signaling axis was examined using molecular and pharmacological approaches. RNA sequencing, pathway enrichment, lysosome- and metabolism-related transcriptional analyses, and secretory profiling were performed to characterize efferocytosis-induced MGCs. Their effects on colorectal cancer cells and the tumor microenvironment were further evaluated in vitro and in tumor-bearing mouse models. Excessive apoptotic cell burden markedly promoted macrophage fusion and upregulated the fusion-related molecules DCSTAMP/Dcstamp and CDH1/Cdh1. Apoptotic cell overload shifted macrophages from a homeostatic/efferocytic state toward a fusion-prone MGC phenotype. TYROBP/Tyrobp knockdown or loss inhibited macrophage fusion. Mechanistically, apoptotic cell overload activated the TREM2/TYROBP-MAPK/c-FOS-DCSTAMP axis, thereby enhancing DCSTAMP transcription and macrophage fusion. Efferocytosis-induced MGCs showed reduced lysosome-related transcriptional programs and an altered secretory profile, including increased TNF-α expression. Functionally, MGCs inhibited colorectal cancer cell growth in vitro. In tumor-bearing mice, MGCs reduced CD206⁺ macrophage and regulatory T-cell abundance while increasing CD8⁺ T-cell infiltration, thereby contributing to tumor growth suppression. Together, these findings identify efferocytosis-induced MGCs as a distinct macrophage state with altered lysosomal and secretory programs, anti-tumor activity, and the potential to remodel the tumor microenvironment.</p>","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"17 1","pages":""},"PeriodicalIF":12.2,"publicationDate":"2026-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13694713/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149243214","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":"Retraction Note: Knockdown of linc-UFC1 suppresses proliferation and induces apoptosis of colorectal cancer.","authors":"T Yu, T-D Shan, J-Y Li, C-Z Huang, S-Y Wang, H Ouyang, X-J Lu, J-H Xu, W Zhong, Q-K Chen","doi":"10.1038/s41419-026-09339-z","DOIUrl":"https://doi.org/10.1038/s41419-026-09339-z","url":null,"abstract":"","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"17 1","pages":""},"PeriodicalIF":12.2,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13631333/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149104550","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":"Galectin-3 restrains T cell-driven inflammation in the testis and epididymis.","authors":"Hiba Hasan, Kimberly Jandel, Eva Wahle, Gabriela Michel, Linda Kreyling, Vishnu Kumar, Tara Procida-Kowalski, Sudhanshu Bhushan, Michaela Frolikova, Jens Rosellen, Thorsten Diemer, Katerina Komrskova, Marek Bartkuhn, Martin Speckmann, Hans-Christian Schuppe, Daniela Fietz, Christiane Pleuger, Andreas Meinhardt, Monika Fijak","doi":"10.1038/s41419-026-09304-w","DOIUrl":"10.1038/s41419-026-09304-w","url":null,"abstract":"<p><p>Galectin-3 (Gal-3) is a pleiotropic molecule involved in immune regulation and tissue homeostasis. While it has been implicated in reproductive tissue function, its role in shaping immune cell dynamics within the testis and epididymis remains incompletely defined. Here, we investigated the function of Gal-3 in the testis and epididymis under steady-state and inflammatory conditions, to determine its contribution to inflammatory responses and tissue damage. In both murine and human tissues, Gal-3 frequency and staining intensity increased along the testicular-epididymal axis, with the highest proportion of Gal-3⁺ cells in the cauda epididymidis, where it was detected across multiple murine immune cell populations, as well as epithelial and germ cells. Consistent with this distribution, Gal-3 deficiency reshaped the local immune landscape, leading to reduced macrophage populations and increased T cell abundance in the testis and cauda epididymidis. In a model of experimental autoimmune epididymo-orchitis (EAEO), Gal-3-deficient (Lgals3^-/-) mice exhibited exacerbated inflammation, fibrosis, and irreversible organ damage, accompanied by increased T cell frequencies among CD45⁺ cells. Transcriptomic analysis revealed enhanced T cell activation signatures, particularly involving IFN-γ-related pathways. Functionally, Gal-3-deficient T cells showed increased cytokine production, specifically IFN-γ, which was further amplified in the presence of Gal-3-deficient macrophages, which in turn acquired a pro-inflammatory phenotype. Together, these findings identify Gal-3 as a key regulator of T cell activity and macrophage polarization with prominent effects in the testis and epididymis, with implications for understanding immune-mediated infertility.</p>","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"17 1","pages":""},"PeriodicalIF":12.2,"publicationDate":"2026-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13615981/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149058597","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}