Cell Death Discovery最新文献

{"title":"CDC73 suppresses lung adenocarcinoma via the PTEN/AKT pathway and exhibits biomarker and functional potential in extracellular vesicles.","authors":"Hao Dong, Yifan Zheng, Gaoming Wang, Xingyi Li, Jing Luo, Jingjing Feng, Xiaohui Zhu, Chongjun Zhong, Yiming Xu, Tian Xie, Yi Shen","doi":"10.1038/s41420-026-03305-6","DOIUrl":"10.1038/s41420-026-03305-6","url":null,"abstract":"<p><p>CDC73 is a canonical tumor suppressor; however, its biological functions in lung adenocarcinoma (LUAD) and the extracellular vesicle (EV)-mediated mechanisms through which it exerts its effects remain unclear. In this study, we systematically evaluated the diagnostic value, biological functions, and EV-mediated regulatory roles of CDC73 in LUAD. First, quantitative proteomic analysis was performed on plasma-derived EVs from six patients with early-stage LUAD and three healthy donors, followed by further validation of EV-borne CDC73 expression in plasma-derived EV samples from eight LUAD patients and eight healthy donors. We found that the level of EV-borne CDC73 protein (EV-CDC73) was significantly reduced in LUAD, indicating its potential value as a diagnostic liquid-biopsy biomarker. To define its functional role, we established LUAD cell lines stably overexpressing CDC73 (A549^OE and H1299^OE) and performed rescue experiments in combination with PTEN knockdown using siRNA. The tumor-suppressive effects of CDC73 were systematically assessed through experiments examining cell proliferation, cell-cycle progression, apoptosis, migration, and related molecular mechanisms. Meanwhile, EVs were isolated by ultracentrifugation from the conditioned media of A549, H1299, and human bronchial epithelial (HBE) cells to analyze the effects of EVs with different CDC73 levels on recipient A549 and HBE cells, and xenograft models were used for in vivo validation. The results showed that CDC73 overexpression markedly inhibited LUAD cell proliferation and migration, induced G1-phase arrest, and promoted apoptosis. Mechanistically, CDC73 exerted its tumor-suppressive effects by upregulating PTEN and inhibiting AKT activation, whereas PTEN knockdown partially reversed these effects. In vivo experiments further confirmed that CDC73 overexpression suppressed tumor growth and migration. In addition, EVs derived from LUAD cells with high CDC73 expression showed a reduced ability to induce malignant transformation-related phenotypes in HBE cells and suppressed the PTEN/AKT signaling axis; conversely, EVs derived from HBE cells with high CDC73 expression inhibited the malignant progression of LUAD cells. Collectively, CDC73 suppresses the malignant progression of LUAD through the PTEN/AKT signaling axis, while EV-borne CDC73 not only has potential diagnostic value but also directly regulates malignant phenotypes in recipient cells, highlighting its translational potential in the diagnosis and treatment of LUAD.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":"12 1","pages":""},"PeriodicalIF":10.4,"publicationDate":"2026-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13652814/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149148042","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":"C2ORF68 stabilizes SIVA1 to upregulate BCL-2 and suppress apoptosis in gallbladder cancer.","authors":"Xuanjia Dong, Lingxiao Zhang, Wenjun Dong, Qiuyi Tang, Jingwei Zhao, Zhaohui Jin, Lin Jiang, Wenting Dai, Yangyang Zhai, Ying Huang","doi":"10.1038/s41420-026-03279-5","DOIUrl":"10.1038/s41420-026-03279-5","url":null,"abstract":"<p><p>Gallbladder cancer (GBC) is the most aggressive malignancy of the biliary tract, and its molecular drivers remain insufficiently understood. SIVA1 (apoptosis regulatory protein Siva 1) has been implicated in the regulation of cell survival, but its function in GBC has not been defined. In this study, we found that SIVA1 expression was elevated in GBC tissues and cell lines, and high SIVA1 expression was associated with poor patient prognosis. Gain- and loss-of-function experiments demonstrated that SIVA1 promoted GBC cell proliferation and migration in vitro and facilitated tumor growth in nude mice xenograft model. Mechanistically, SIVA1 was subject to ubiquitin-proteasome-mediated degradation, and we identified C2ORF68 as a binding partner that reduced SIVA1 ubiquitination and stabilized its protein level. Stabilized SIVA1 in turn increased the expression of the anti-apoptotic protein BCL-2, thereby enhancing cell survival. These findings indicate that C2ORF68-mediated stabilization of SIVA1 promotes GBC progression through BCL-2-dependent anti-apoptotic signaling, supporting SIVA1 as a potential therapeutic target.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":"12 1","pages":""},"PeriodicalIF":10.4,"publicationDate":"2026-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13652811/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149147540","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":"Physiological re-replication during human stem cell differentiation.","authors":"Marie Minet, Amila Beganovic, Shusruto Rishik, Elisa Michaeli, Daniela Yildiz, Georges P Schmartz, Paula E Schwarz, Melina Schäfer, Tanja Tänzer, Magali Cucchiarini, Nicole Ludwig, Andreas Keller, Eckart Meese, Ulrike Fischer","doi":"10.1038/s41420-026-03267-9","DOIUrl":"10.1038/s41420-026-03267-9","url":null,"abstract":"<p><p>During restricted timeframes in Drosophila development, re-replication occurs as physiological process causing the known developmental gene amplification in Drosophila. Gene amplification has also been found during differentiation in human stem cells but re-replication in human cells has been preferentially associated with tumor related genome instability. Here, we show that re-replication also occurs as physiological process in human stem cells. We used Rerep-Seq and fiber-combing to demonstrate re-replication during the differentiation of human myoblasts into myotubes and during the differentiation of mesenchymal stem cells into adipocytes, osteoblasts, chondrocytes, and neurons. Re-replication was detectable during specific timeframes in all differentiations analyzed. FACS sorting of re-replicating cells showed increased gene expression in re-replicated genome regions. Additionally, re-replicated DNA was identified as extranuclear DNA. This leads us to the hypothesis that cells that do not re-replicate and thus do not face an increased risk of chromosomal instability may ensure higher expression of certain genes and their encoded proteins during differentiation by incorporating re-replicated DNA from neighbouring cells with re-replication. We propose that human stem cells use an ancient re-replication mechanism to efficiently increase gene copy numbers, thereby meeting the heightened protein demands during differentiation.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":"12 1","pages":""},"PeriodicalIF":10.4,"publicationDate":"2026-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13421607/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148618507","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":"Transcriptomic analysis reveals that neural stem cell-derived exosomes regulate the HMGB1/TLR2 signaling axis to promote astrocytic differentiation and mitochondrial biogenesis in the repair of radiation-induced blood-brain barrier damage.","authors":"Fanrui Zeng, Yalei Zhang, Yun Zhou, Zichen Ma, Chenghao Li, Guohua Yao, Rong Li","doi":"10.1038/s41420-026-03250-4","DOIUrl":"10.1038/s41420-026-03250-4","url":null,"abstract":"<p><p>Radiation-induced brain injury (RBI) is frequently associated with blood-brain barrier (BBB) disruption, which contributes to poor prognosis. Neural stem cell-derived exosomes (NSC-Exo) have recently attracted attention as mediators of intercellular communication with potential roles in tissue repair. However, how NSC-Exo promote BBB recovery after RBI remains unclear. This study explored whether NSC-Exo restore BBB function by regulating the HMGB1/TLR signaling pathway, thereby promoting endogenous NSC differentiation toward astrocytes and enhancing mitochondrial biogenesis. A rat RBI model was established and treated with NSC-Exo. Molecular marker analysis, transcriptomic profiling, and BBB functional assessment were performed to clarify the underlying mechanisms. The results showed that NSC-Exo enhanced NSC stemness and astrocytic differentiation, improved mitochondrial function, and reduced ROS accumulation. NSC-Exo also suppressed HMGB1/TLR2 pathway activation and promoted BBB repair. Functional experiments further indicated that HMGB1 overexpression weakened the protective effects of NSC-Exo, whereas TLR2 knockdown reversed this effect. In conclusion, NSC-Exo facilitate endogenous NSC remodeling and BBB restoration after RBI, at least partly through regulation of the HMGB1/TLR2 axis, providing a potential strategy for RBI treatment. Schematic illustration of the molecular mechanism by which NSC-Exo ameliorates RBI through inhibition of the HMGB1/TLR2 signaling pathway.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":"12 1","pages":""},"PeriodicalIF":10.4,"publicationDate":"2026-07-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13575103/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148966645","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":"Targeting androgen receptor as a novel radiosensitizing therapy to improve long-term survival and anti-tumor immunity in glioblastoma via TGF-β/Smad3 Axis reprogramming.","authors":"Jyoti B Kaushal, Nan Zhao, Rubayat Khan, Kan Liu, Chi Zhang, Fei Wang, Jie Chen, Bingjie Guan, Shuo Wang, Tom K Hei, Tony J C Wang, Yuguo Lei, Michele R Aizenberg, Chi Lin, Chi Zhang","doi":"10.1038/s41420-026-03259-9","DOIUrl":"https://doi.org/10.1038/s41420-026-03259-9","url":null,"abstract":"<p><p>Glioblastoma (GBM) remains the most aggressive primary adult brain cancer with limited therapeutic options. Our prior research demonstrated that androgen receptor antagonists (ARAs) enhance survival in GBM mouse models by preferentially suppressing glioma stem cells. This study investigates the potential of ARAs as radiosensitizers in combination with radiotherapy (RT). Combined effects of ARAs and RT were evaluated using an orthotopic GBM mouse model. RNA-Seq and TCGA analyses delineated AR-associated regulatory networks, while integrated cellular and molecular approaches utilizing human and mouse GBM cell lines, as well as in patient-derived primary high-grade glioma cultures, interrogated signaling and immune paradigms. ARA treatment induced G2/M cell cycle arrest, apoptosis, and downregulated DNA repair genes, with AR expression correlating with the DNA repair and TGF-β pathway. In both immortalized GBM cell lines and primary high-grade glioma cultured cells, ARAs in combination with RT showed only a modest enhancement of radiosensitivity. However, in an orthotopic GBM mouse model, ARA + RT demonstrated a strong synergy, achieving 100% long-term survival, compared to less than 50% with ARA alone and 0% with RT alone. Mechanistically, ARA modulated the TGF-β pathway, durably switching from Smad3 linker to c-terminal phosphorylation (pSmad3C) and inhibiting the LIF/STAT3 axis. Distinct TGF-βs ligand expression patterns were observed in ARA-treated GBM cells. A protein-protein interaction noted between AR and pSmad3, which was disrupted following ARA treatment, leading to elevated protein levels and nuclear localization of pSmad3C (S423/425), indicating normalization/activation of the TGF-β/pSmad3C-dependent anti-tumorigenic cascade. Comprehensive analyses in GBM cell lines and mouse model tissues demonstrated pathway reprogramming characterized by elevated TGF-β2 and increased pSmad3C. Rescue experiments using a TGFβRII degrader with ARA abolished pSmad3C phosphorylation, confirming the functional significance of TGFβRII/pSmad3C axis. Tissue analysis revealed immune activation in the tumor microenvironment, while peripheral blood and spleen showed systemic immune responses following ARA + RT. Our study provides novel insights into how ARAs enhance RT efficacy through immunomodulation involving TGF-β/pSmad3C cascade, offering therapeutic implications in GBM.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":"12 1","pages":""},"PeriodicalIF":10.4,"publicationDate":"2026-07-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149227427","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":"The sperm survival switch: circRNA-mediated regulatory loops control apoptotic signalling in human spermatozoa.","authors":"Alice Luddi, Antonella Migliaccio, Matteo Prisinzano, Teresa Chioccarelli, Eugenia Annunzi, Francesca Paola Luongo, Francesca Girolamo, Maryam Raeispour, Bodo Levkau, Guillaume Martinez, Charles Coutton, Michele Caraglia, Caterina Bernacchioni, Gilda Cobellis, Chiara Donati, Francesco Manfrevola, Rosanna Chianese, Paola Piomboni","doi":"10.1038/s41420-026-03262-0","DOIUrl":"10.1038/s41420-026-03262-0","url":null,"abstract":"<p><p>Male reproductive health is declining worldwide, partly due to lifestyle factors including obesity, which is linked to increased sperm apoptosis and impaired assisted reproductive technologies (ARTs) outcomes. This growing issue underscores the urgent need for novel molecular biomarkers capable of improving sperm quality assessment. In this context, circular RNAs (circRNAs) are emerging as regulators of germ cell functions and apoptosis, but their role as early apoptotic markers in human sperm under lifestyle-related stress remains poorly explored. In this study, by using the obesity as experimental condition of sperm apoptosis-induction, we performed a comprehensive circRNA profiling in High-quality spermatozoa (A-SPZ) collected from Normal-weight and Obese men. Obese sperm exhibit a pro-apoptotic phenotype associated with a cargo of differentially expressed (DE-) circRNAs enriched in pro-apoptotic regulatory networks. Mechanistically, circRNAs arise both from the trigger of FUS-regulated endogenous backsplicing and via extracellular vesicles (EVs) mediated delivery, thereby establishing a functional pro-apoptotic circRNA regulatory circuit. Furthermore, Obese men exhibit a dysregulated sphingosine 1-phosphate (S1P) signaling axis, along with an imbalanced S1P-to-ceramide rheostat within EVs and increased levels of pro-apoptotic ceramide. Finally, the in vitro sperm apoptosis induction confirmed a functional circRNA-apoptosis axis, identifying a subset of circRNAs responsive to pro-apoptotic stimuli that engage in a self-reinforcing regulatory loop involving pro-CASPASE3 activation. Our findings elucidate a pro-apoptotic propensity in Obese A-SPZ positioning circRNAs as putative molecular biomarkers candidate for early apoptosis. These spermatic circRNAs, which are significantly up-regulated under apoptotic conditions, exert a dual functional role: (i) serving as diagnostic markers for early-stage apoptosis and (ii) acting as active molecular adapters to enhance apoptosis activation. These circRNAs could be suggested as early sperm apoptotic biomarkers enhancing the precision of sperm quality assessment and, in turn, the success of ART procedures.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":"12 1","pages":""},"PeriodicalIF":10.4,"publicationDate":"2026-07-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13562583/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148929142","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":"Age- and sex-dependent retinal degeneration in peripherin-2 mutant mice, a model of central areolar choroidal dystrophy.","authors":"Enola Missonnier, Lorena Vidal-Gil, Carla Sánchez-Castillo, Estela Tébar-Garcerán, Ceren Sahin, Marina Pastor-Mas, Yoel Hernández, Oksana Kutsyr, Laura Fernández-Sánchez, Victoria Maneu, Nicolás Cuenca, Natalia Martínez-Gil","doi":"10.1038/s41420-026-03263-z","DOIUrl":"https://doi.org/10.1038/s41420-026-03263-z","url":null,"abstract":"<p><p>Central areolar choroidal dystrophy (CACD) is a progressive macular dystrophy without treatment. Although PRPH2 mutations are the most common cause of disease, the mechanisms driving their phenotypic variability remain poorly understood. Here, a comprehensive characterization of the pathophysiological consequences of p.Arg195Leu mutation in PRPH2 was carried out in a mouse model (Prph2^KI/WT). For evaluating the retinal degeneration, this study combines the analysis of electroretinographic responses together with a complete study of bulk RNA-seq transcriptomics and the key cellular and molecular pathways using confocal imaging, flow-cytometry and western blotting. Results from this work demonstrate that ageing and sex influence retinal degeneration. In young mutant mice, retinal functional impairment and structural disorganization of photoreceptor outer segments were accompanied by a reduced expression of Prph2 and Rom1 genes, together with the activation of the immune system and complement pathways. Middle-age stages represent a critical transition point where the increase of cell death and epithelial barrier dysfunction mark the beginning of retinal degeneration. These pathological events become evident at 9 months of age, where visual pathways-related genes were deregulated. Functional, cellular and molecular alterations observed in the mutant mice do not affect males and females equally. From the earliest stages of the disease, females exhibited greater and sustained inflammatory activation, mainly promoted by complement system upregulation and increased CD11b immunoreactivity, and potentially mediated by IL-6/STAT3/ERK signaling. Moreover, females had greater functional decline and photoreceptor loss. Together, these results could explain the high inter- and intrafamilial variability observed in CACD patients carrying the same mutation. Our findings identify inflammatory biomarkers accompanied by visual function loss, prior to evident retinal degeneration, and demonstrate that age and sex critically shape disease onset and severity. These insights underscore the necessity of incorporating sex-specific biology and early anti-inflammatory treatment into the development of targeted therapies for PRPH2-related dystrophies.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":"12 1","pages":""},"PeriodicalIF":10.4,"publicationDate":"2026-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149223352","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":"OTUB1 inhibits autophagy-dependent ferroptosis in hepatocellular carcinoma by stabilizing p62 via non-canonical deubiquitination.","authors":"Pengcheng Zhao, Yongxin Wang, Nima Saeidi, Ping Zhang","doi":"10.1038/s41420-026-03241-5","DOIUrl":"10.1038/s41420-026-03241-5","url":null,"abstract":"<p><p>Ubiquitination plays a critical role in hepatocellular carcinoma (HCC) pathogenesis and is closely linked to ferroptosis. This study investigates the function of OTUB1, a deubiquitinase overexpressed in HCC, in regulating autophagy-dependent ferroptosis. Using integrated bioinformatics, biochemical assays, and xenograft models, we demonstrated that OTUB1 is upregulated in HCC and correlates with poor prognosis. Functionally, OTUB1 knockdown suppressed proliferation and induced ferroptosis, whereas its overexpression promoted malignancy. Mechanistically, OTUB1 competitively binds to p62/SQSTM1, thereby suppressing autophagic flux. Crucially, we identified that OTUB1 stabilizes p62 via non-canonical, D88-dependent deubiquitination by specifically removing K48-linked polyubiquitin chains. This stabilization hinders the initiation of autophagy-dependent ferroptosis. Pharmacological inhibition of autophagy abrogated the ferroptosis induced by OTUB1 knockdown. Furthermore, inhibiting OTUB1 sensitized HCC tumors to Lenvatinib, resulting in synergistic anti-tumor efficacy in vivo. Collectively, these findings reveal that OTUB1 drives HCC progression by stabilizing p62 to block autophagy-dependent ferroptosis. Targeting the OTUB1-p62 axis represents a novel therapeutic strategy to overcome drug resistance and improve outcomes in advanced HCC.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":"12 1","pages":""},"PeriodicalIF":10.4,"publicationDate":"2026-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13601636/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149029978","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":"PIN1 enhances SUMOylation of YAP1 and inhibits ferroptosis via autophagy-dependent degradation of ACSL4 in cervical cancer.","authors":"Dan Liao, Lijuan Shi, Yumeng Cui, Cuifen Li, Yuhong Yao, Polin Feng, Huali Wang, Haohai Huang","doi":"10.1038/s41420-026-03257-x","DOIUrl":"10.1038/s41420-026-03257-x","url":null,"abstract":"<p><p>Cervical cancer (CC) is a prevalent malignancy threatening women's health. Due to its complex pathogenesis and tumor heterogeneity, it is urgent to thoroughly investigate its pathological mechanisms. Based on the TCGA database, the expression and survival analysis of PIN1 and YAP1 were assessed in CC. To verify their roles in regulating CC, stable knockdown and overexpression cell lines were constructed in CC cell lines. In vivo and in vitro experiments were conducted to verify that PIN1 regulates YAP1's SUMOylation levels and induces ACSL4's autophagic degradation. This research shows that PIN1 binds to YAP1, promoting its SUMOylation and causing autophagy-mediated degradation of ACSL4, enabling cervical cancer cells to resist ferroptosis. In vivo xenograft models confirm these findings. This study identifies PIN1 as a key redox-balance node and presents it as a potential therapeutic target for CC ferroptosis. Inhibiting PIN1 and YAP1 can inhibit tumor progression, offering a promising approach for treating aggressive CC.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":" ","pages":""},"PeriodicalIF":10.4,"publicationDate":"2026-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13672308/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148547904","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":"Cytokine-induced expandable memory NK cells with significant metabolic, epigenetic remodeling, and persistence properties.","authors":"Hongye Wang, Jingwei Tu, Yi Luo, Xinxin Yuan, Xin Fang, Zhengyi Lu, Li Han, Yongjia Xue, Wencheng Zhang, Qianggang Dong, Zhiying He","doi":"10.1038/s41420-026-03260-2","DOIUrl":"10.1038/s41420-026-03260-2","url":null,"abstract":"<p><p>Recent investigations have indicated that NK cells induced overnight with IL-12/15/18 cytokines possess memory-like characteristics (refers as CIML NK, cytokine induced memory-like NK cells), demonstrating enhanced effector function and prolonged persistence. Preclinical studies and very early clinical trials revealed the promising clinical activity of CIML NK cells in the treatment of hematological malignancies, especially acute myelocytic leukemia (AML). However, the current manufacturing method for CIML NK cells do not endow these cells the ability to expand robustly ex vivo. The low production efficiency limits their clinical application. In this study, we established a novel expansion platform for generating memory-like NK cells by first inducing memory properties through stimulation with CD16a, IL-15, and IL-18, followed by a robust expansion phase. This method can effectively and stably expand healthy donor-derived Peripheral NK (PBNK) cells by more than 200-fold within two weeks, with a purity exceeding 95%. Importantly, these ex vivo expanded NK (ExNK) cells exhibited hypomethylated state in the CNS-1 region (Conserved Noncoding Sequence 1) of IFNG gene, stronger metabolic ability, and enhanced effector function when compared to CIML NK cells. Based on these features, we named these expanded NK cells but still possess memory-like characteristics as mExNK (memory-like expanded NK cells). Bulk mRNA-seq further uncovered a high similarity between mExNK and CIML NK cells, with both highly expressing genes being related to proliferation, metabolism, and memory. Mouse tumor models proved that the infused mExNK exhibited longer persistence in vivo and stronger effector functions. Taken together, the method described herein showed an enhanced expansion efficiency for human CIML NK cells and would facilitate their clinic applications in cancer therapy.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":" ","pages":""},"PeriodicalIF":10.4,"publicationDate":"2026-07-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13672343/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148547944","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}