Cell Death Discovery最新文献_第5页

Targeting the ODC1-YBX1 axis reverses gastric cancer chemoresistance via transcriptional control of SLC7A11-mediated ferroptosis. 靶向ODC1-YBX1轴通过转录控制slc7a11介导的铁下垂逆转胃癌化疗耐药。

IF 7 2区生物学

Cell Death Discovery Pub Date : 2026-04-14 DOI: 10.1038/s41420-026-03067-1

Ruiqi Li, Shantanu Baral, Fanyu Zhao, Chenkai Zhang, Jiajie Zhou, Ben Li, Yifan Cheng, Dengyang Fang, Zijie Xu, Yayan Fu, Jianyue Ding, Zhen Tian, Shuai Zhao, Jie Wang, Mengli Zi, Longhe Sun, Xuetong Jiang, Qiannan Sun, Daorong Wang

{"title":"Targeting the ODC1-YBX1 axis reverses gastric cancer chemoresistance via transcriptional control of SLC7A11-mediated ferroptosis.","authors":"Ruiqi Li, Shantanu Baral, Fanyu Zhao, Chenkai Zhang, Jiajie Zhou, Ben Li, Yifan Cheng, Dengyang Fang, Zijie Xu, Yayan Fu, Jianyue Ding, Zhen Tian, Shuai Zhao, Jie Wang, Mengli Zi, Longhe Sun, Xuetong Jiang, Qiannan Sun, Daorong Wang","doi":"10.1038/s41420-026-03067-1","DOIUrl":"https://doi.org/10.1038/s41420-026-03067-1","url":null,"abstract":"Gastric adenocarcinoma (STAD), a leading cause of cancer mortality, faces major therapeutic challenges due to intrinsic and acquired chemoresistance. Chemoresistance is intricately linked to ferroptosis.Elucidating the mechanisms of chemotherapy resistance in STAD represents a critical unmet need to improve patient survival. This study identifies ODC1 as a crucial driver of 5-Fu resistance and suppressor of ferroptosis in STAD. Multi-dataset analysis revealed significant ODC1 overexpression in STAD tissues, correlating with advanced stage and poor survival. Functionally, ODC1 depletion inhibited proliferation, migration, invasion, and tumor growth in vitro and in vivo, while its overexpression exacerbated malignant phenotypes. Critically, ODC1 was upregulated in 5-Fu-resistant cell models, and its knockdown restored chemosensitivity by triggering ferroptosis-an iron-dependent cell death characterized by lipid peroxidation, glutathione depletion, and malondialdehyde accumulation. Mechanistically, ODC1 interacts with transcription factor YBX1 through its PLPDE_III_ODC domain. This complex binds the promoter of SLC7A11, enhancing its transcription. YBX1 silencing phenocopied ODC1 knockdown, increasing ferroptosis susceptibility; conversely, SLC7A11 overexpression or GPX4 activation (via ML334) reversed ferroptosis induced by ODC1/YBX1 inhibition. Significantly, Erastin-a SLC7A11 inhibitor-overcame YBX1-mediated resistance, synergizing with 5-Fu to induce ferroptosis and suppress tumor growth. Collectively, we unveil the ODC1-YBX1-SLC7A11-ferroptosis axis as a central mechanism of chemoresistance in STAD. Targeting this axis-via ODC1 inhibition or ferroptosis induction-represents a novel therapeutic strategy to reverse treatment resistance in gastric adenocarcinoma.","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":" ","pages":""},"PeriodicalIF":7.0,"publicationDate":"2026-04-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147688359","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}

引用次数: 0

BIRC3/CAV1 co-expression drives GBM aggressiveness as a prognostic signature and therapeutic vulnerability. BIRC3/CAV1共表达驱动GBM侵袭性作为预后标志和治疗脆弱性。

IF 7 2区生物学

Cell Death Discovery Pub Date : 2026-04-14 DOI: 10.1038/s41420-026-03112-z

Sara Franceschi, Mariangela Morelli, Francesca Lessi, Francesca Di Lorenzo, Paolo Aretini, Aldo Pastore, Andrea Marranci, Carlo Gambacciani, Francesco Pieri, Federico Villanacci, Nicola Montemurro, Manuel Giacomarra, Michele Menicagli, Gianmarco Ferri, Francesco Pasqualetti, Marco Krengli, Marc Sanson, Alberto Picca, Anna Luisa Di Stefano, Orazio Santo Santonocito, Chiara Maria Mazzanti

{"title":"BIRC3/CAV1 co-expression drives GBM aggressiveness as a prognostic signature and therapeutic vulnerability.","authors":"Sara Franceschi, Mariangela Morelli, Francesca Lessi, Francesca Di Lorenzo, Paolo Aretini, Aldo Pastore, Andrea Marranci, Carlo Gambacciani, Francesco Pieri, Federico Villanacci, Nicola Montemurro, Manuel Giacomarra, Michele Menicagli, Gianmarco Ferri, Francesco Pasqualetti, Marco Krengli, Marc Sanson, Alberto Picca, Anna Luisa Di Stefano, Orazio Santo Santonocito, Chiara Maria Mazzanti","doi":"10.1038/s41420-026-03112-z","DOIUrl":"https://doi.org/10.1038/s41420-026-03112-z","url":null,"abstract":"Glioblastoma (GBM) is an incurable tumor where temozolomide (TMZ) resistance limits survival, even in MGMT-methylated patients. To improve stratification, we used NAD(P)H-FLIM to profile TMZ response in 35 patient-derived explants, integrating these data with transcriptomic and functional analyses. We identified BIRC3 and CAV1 upregulation in resistant tumors and investigated their parallel yet functionally cooperative role in driving an aggressive, therapy-resistant phenotype. In silico survival analyses demonstrated that BIRC3 and CAV1 act as independent prognostic factors whose additive, non-linear effects robustly stratify patient survival beyond MGMT status, defining a subgroup with <7% 24-month survival. Importantly, BIRC3/cIAP2-driven resistance proved targetable; the IAP antagonist AZD5582 restored TMZ sensitivity by unlocking the apoptotic execution phase, thereby inducing cell death in resistant GBM models in vitro and ex vivo. Our findings establish the BIRC3/CAV1 axis as a key prognostic signature and therapeutic vulnerability in GBM, offering a new path for precision oncology strategies.","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":" ","pages":""},"PeriodicalIF":7.0,"publicationDate":"2026-04-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147670855","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}

引用次数: 0

Correction: Long range inter-chromosomal interaction of Oct4 distal enhancer loci regulates ESCs pluripotency. 更正：Oct4远端增强子位点的远距离染色体间相互作用调节ESCs的多能性。

IF 7 2区生物学

Cell Death Discovery Pub Date : 2026-04-14 DOI: 10.1038/s41420-026-02993-4

Byoung-San Moon, David Huang, Fan Gao, Mingyang Cai, Guochang Lyu, Lei Zhang, Jun Chen, Wange Lu

引用次数: 0

Differentiated SH-SY5Y cells exhibit neuronal features but lack synaptic maturity. 分化的SH-SY5Y细胞具有神经元特征，但缺乏突触成熟度。

IF 7 2区生物学

Cell Death Discovery Pub Date : 2026-04-14 DOI: 10.1038/s41420-026-03094-y

Jana Leuenberger, Grischa Ott, Thomas Nevian, Benoît Zuber, Iman Rostami

{"title":"Differentiated SH-SY5Y cells exhibit neuronal features but lack synaptic maturity.","authors":"Jana Leuenberger, Grischa Ott, Thomas Nevian, Benoît Zuber, Iman Rostami","doi":"10.1038/s41420-026-03094-y","DOIUrl":"https://doi.org/10.1038/s41420-026-03094-y","url":null,"abstract":"A vital question in neuroscience is whether and how efficiently cellular models may be differentiated into functional neuronal cells in culture. Despite the frequent use of the human neuroblastoma cell line SH-SY5Y, differentiation protocols vary extensively, with the most common being differentiation via the addition of retinoic acid and brain-derived neurotrophic factor. However, due to the lack of a reliable evaluation method, their adequacy as synaptic models remains unclear. Here, we investigate whether SH-SY5Y cells constitute a functional model for synaptic studies by phenotypically and ultrastructurally analyzing synaptogenesis in SH-SY5Y cells subjected to different differentiation protocols. Electron microscopy (EM) techniques, including conventional EM, cryo-EM, and cryo-electron tomography, were systematically applied to characterize synaptogenesis in SH-SY5Y cells. Further characterization was performed using immunostaining and functional assays, such as live exocytosis assays and whole-cell patch-clamp electrophysiology. Despite exhibiting some presynaptic-like features, differentiated SH-SY5Y cells do not form morphologically or functionally complete synapses under the conditions tested. Immunostaining results were consistent with previous findings, showing synaptic markers. However, functional investigations did not detect synaptic activity. High-throughput EM analyses revealed an absence of synaptic structures in these cells. Additionally, an alternative differentiation approach incorporating additional neurotrophic factors promoted the formation of presynaptic-like compartments containing synaptic vesicle-like vesicles (SVLVs). In contrast to typical synaptic vesicles, these SVLVs exhibited a pleomorphic size distribution and lacked connectors. These findings underscore the need for cautious interpretation of results derived from SH-SY5Y cells when investigating molecular synaptic architecture or function, as well as neurodegenerative diseases.","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":" ","pages":""},"PeriodicalIF":7.0,"publicationDate":"2026-04-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147688092","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}

引用次数: 0

NT5DC2 inhibits ferroptosis by stabilizing ACSL3 in bladder cancer. NT5DC2通过稳定膀胱癌ACSL3抑制铁下垂。

IF 7 2区生物学

Cell Death Discovery Pub Date : 2026-04-14 DOI: 10.1038/s41420-026-03091-1

Shaorui Niu, Pang Yang, Yuyang Yao, Xiaofeng Tang, Jun Yang, Feifei Zhang, Kangming Chen, Chengli Jiang, Yuhao Zhou, Wei Bai, Liping Li, Yuntong Zhou, Xiao-Bin Lv

{"title":"NT5DC2 inhibits ferroptosis by stabilizing ACSL3 in bladder cancer.","authors":"Shaorui Niu, Pang Yang, Yuyang Yao, Xiaofeng Tang, Jun Yang, Feifei Zhang, Kangming Chen, Chengli Jiang, Yuhao Zhou, Wei Bai, Liping Li, Yuntong Zhou, Xiao-Bin Lv","doi":"10.1038/s41420-026-03091-1","DOIUrl":"https://doi.org/10.1038/s41420-026-03091-1","url":null,"abstract":"Ferroptosis, a form of regulated cell death, plays a pivotal role in the development and treatment of cancer because of its impact on tumor cell proliferation, differentiation, and resistance to chemotherapy. NT5DC2, a gene associated with ferroptosis, has been identified as a key facilitator of cellular proliferation and metastasis in several cancers. In this study, we found that NT5DC2 is highly expressed in bladder cancer tissues compared with normal tissues and that its expression is correlated with the poor prognosis of bladder cancer patients. Functionally, we demonstrated that NT5DC2 suppresses ferroptosis in bladder cancer cells and promotes malignant tumor progression. Mechanistically, NT5DC2 interacts with ACSL3 and hampers its ubiquitination, thereby improving the stability of ACSL3, a crucial ferroptosis suppressing protein induced by oleic acid in lymph nodes. In addition, rescue assay results indicated that ACSL3 mediated the roles of NT5DC2 in suppressing ferroptosis of bladder cancer cells. Furthermore, we found that the upregulation of ACSL3 by oleic acid treatment was mediated by NT5DC2 as manifested by the observation that silencing of NT5DC2 abrogates this regulatory effect of oleic acid treatment. Collectively, our findings suggest that NT5DC2/ACSL3 plays a critical role in bladder cancer progression and ferroptosis regulation, suggesting that NT5DC2/ACSL3 is a potential therapeutic target for bladder cancer treatment.","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":" ","pages":""},"PeriodicalIF":7.0,"publicationDate":"2026-04-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147670847","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}

引用次数: 0

Bon appétit, your phagocyte. Bon appetit, your phagocyte。

IF 7 2区生物学

Cell Death Discovery Pub Date : 2026-04-14 DOI: 10.1038/s41420-026-03099-7

Dilara C Ozkocak, Jascinta P Santavanond, Maria C Tanzer, Ivan K H Poon

{"title":"Bon appétit, your phagocyte.","authors":"Dilara C Ozkocak, Jascinta P Santavanond, Maria C Tanzer, Ivan K H Poon","doi":"10.1038/s41420-026-03099-7","DOIUrl":"https://doi.org/10.1038/s41420-026-03099-7","url":null,"abstract":"Every day, billions of cells in the human body undergo apoptosis as part of normal tissue turnover. The swift clearance of these dying cells by phagocytes is an essential process to limit the release of intracellular contents that can disrupt tissue homeostasis and promote inflammation, autoimmunity, and chronic disease. Thus, as with the unseen yet continuous work of a well-run kitchen, effective apoptotic cell clearance sustains multicellular organisms. In cooking, ingredients must be deliberately gathered, trimmed, seasoned, cooked, and plated before becoming part of a satisfying meal. Analogously, apoptotic cells undergo an equally deliberate 'meal preparation' process in which they transform themselves to be optimally suited for consumption by professional and non-professional phagocytes. This preparation involves a coordinated suite of modifications, including the secretion of immunomodulatory factors, the internal partitioning of organelles, and the exposure of 'eat-me' signals. Additionally, maintaining membrane integrity during apoptosis can be viewed as a 'protective wrapping' that preserves 'edible' cargo while preventing the inflammatory spillover that would result from premature plasma membrane rupture (PMR). In this perspective, we highlight how these distinct, yet interconnected layers of apoptotic cell 'cooking' converge to shape and influence the eventual phagocytic encounter. A deeper understanding of how apoptotic cells prepare themselves for clearance not only reframes our view of cell death, but also offers opportunities to harness or correct these processes in pathological settings where clearance fails.","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":" ","pages":""},"PeriodicalIF":7.0,"publicationDate":"2026-04-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147687946","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}

引用次数: 0

Correction: CLC3 regulates V-ATPase to enhance lysosomal degradation and cisplatin resistance in cervical cancer cells. 更正：CLC3调节v - atp酶，增强宫颈癌细胞溶酶体降解和顺铂耐药。

IF 7 2区生物学

Cell Death Discovery Pub Date : 2026-04-14 DOI: 10.1038/s41420-026-03008-y

Chuyun Chen, Fubin Zhang, Jiayi Shen, Qi Zheng, Zhiyun Zhang, Shun Lu, Lixiao Liu, Tianhong Zhu, Yongming Du, Yutao Guan

引用次数: 0

Oncoprotein CYB561, acting in IRE1-XBP1-SREBF1 and FAK-ERK pathway, promotes breast cancer lipogenesis and progression. 癌蛋白CYB561参与IRE1-XBP1-SREBF1和FAK-ERK通路，促进乳腺癌脂肪生成和进展。

IF 7 2区生物学

Cell Death Discovery Pub Date : 2026-04-13 DOI: 10.1038/s41420-026-03101-2

Xiaochen Yang, Yukai Tao, Yan Xu, Qixiang Shao, Guoqin Jiang

{"title":"Oncoprotein CYB561, acting in IRE1-XBP1-SREBF1 and FAK-ERK pathway, promotes breast cancer lipogenesis and progression.","authors":"Xiaochen Yang, Yukai Tao, Yan Xu, Qixiang Shao, Guoqin Jiang","doi":"10.1038/s41420-026-03101-2","DOIUrl":"https://doi.org/10.1038/s41420-026-03101-2","url":null,"abstract":"Breast cancer (BC) heterogeneity, particularly in triple-negative (TNBC) and HER2-positive subtypes, underpins therapeutic challenges and cancer-related mortality worldwide. Here, we identify the transmembrane oxidoreductase CYB561 as a pivotal oncoprotein that drives BC malignancy by coordinating lipid metabolic reprogramming and oncogenic signaling. CYB561 was significantly overexpressed in BC tissues, especially in HER2-positive (70%) and TNBC (60%) cases, and its expression correlated with advanced T stage, metastasis, and poor patient survival. Functionally, CYB561 potently promoted proliferation, migration, invasion, epithelial-mesenchymal transition (EMT), and tumor growth in vitro and in vivo. Mechanistically, CYB561 directly bound IRE1, triggering the IRE1-XBP1-SREBF1 axis to induce lipogenic enzyme expression and lipid droplet accumulation. Concurrently, it activated the FAK-ERK signaling pathway. Crucially, IRE1 knockdown abolished CYB561-induced lipogenesis and malignant phenotypes, while ERK inhibition partially attenuated these effects, revealing a synergistic crosstalk between metabolic and signaling axes. Our findings establish CYB561 as a master regulator of BC progression and nominate it as a promising therapeutic target for aggressive breast cancers.","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":" ","pages":""},"PeriodicalIF":7.0,"publicationDate":"2026-04-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147670814","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}

引用次数: 0

Long term administration of selective NMDA GluN2B receptor blocker Ro25-6981 attenuates neurodegeneration in mouse model of spinocerebellar ataxia type 1 (SCA1). 长期给予选择性NMDA GluN2B受体阻滞剂Ro25-6981可减轻1型脊髓小脑性失调（SCA1）小鼠模型的神经退行性变。

IF 7 2区生物学

Cell Death Discovery Pub Date : 2026-04-13 DOI: 10.1038/s41420-026-03120-z

Olga S Belozor, Alexandra G Mileiko, Lyudmila D Mosina, Ilya G Mikhailov, Milana S Mikhailova, Elena D Khilazeva, Darius A Ox, Egor S Grinev, Elizaveta B Boitsova, Andrey N Shuvaev, Anja G Teschemacher, Sergey Kasparov, Anton N Shuvaev

{"title":"Long term administration of selective NMDA GluN2B receptor blocker Ro25-6981 attenuates neurodegeneration in mouse model of spinocerebellar ataxia type 1 (SCA1).","authors":"Olga S Belozor, Alexandra G Mileiko, Lyudmila D Mosina, Ilya G Mikhailov, Milana S Mikhailova, Elena D Khilazeva, Darius A Ox, Egor S Grinev, Elizaveta B Boitsova, Andrey N Shuvaev, Anja G Teschemacher, Sergey Kasparov, Anton N Shuvaev","doi":"10.1038/s41420-026-03120-z","DOIUrl":"https://doi.org/10.1038/s41420-026-03120-z","url":null,"abstract":"Spinocerebellar ataxia type 1 (SCA1) is caused by a CAG expansion in the gene that encodes the protein Ataxin1. Accumulation of the mutant protein in cells leads to degeneration of the cerebellum and brainstem, resulting in ataxia and culminates in failure of the circuits controlling swallowing and breathing. The nonselective NMDA receptor blocker memantine has been proposed as a potential treatment for SCA1, as it reduces excitotoxicity and neurodegeneration in other murine models of neurodegeneration. However, side effects of memantine limit its therapeutic potential, highlighting the need for more selective treatments. We have developed an SCA1 model where a lentiviral vector (LVV) selectively expresses mutant Ataxin1 in cerebellar astrocytes, triggering neuronal death through glial dysfunction and NMDA receptor-mediated excitotoxicity. Using this model, we investigate the effects of long-term administration of Ro25-6981, a selective blocker of the GluN2B subunit of glutamate receptors, typically found on extrasynaptic NMDA receptors. Chronic administration of Ro25-6981 (0.5 mg/kg day intraperitoneally) for 4 weeks prevented deterioration of motor activity in SCA1 model mice, an effect, associated with reduced neurodegeneration and decreased reactivity of Bergmann glia in the cerebellar cortex. Moreover, short-term endocannabinoid-mediated plasticity was partially preserved. Long-term blockade of NMDA receptors with Ro25-6981 caused a compensatory upregulation of expression of GluN2B and NR2A subunits. These findings suggest that specific targeting of extrasynaptic NMDA receptors with Ro25-6981 or similar drugs might offer a viable therapeutic strategy for treatment of SCA1.","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":" ","pages":""},"PeriodicalIF":7.0,"publicationDate":"2026-04-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147670829","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}

引用次数: 0

Dual control of liver regeneration by Nr1d1 homeostasis and Klf2 checkpoint. Nr1d1稳态和Klf2检查点对肝脏再生的双重控制。

IF 7 2区生物学

Cell Death Discovery Pub Date : 2026-04-13 DOI: 10.1038/s41420-026-03039-5

Bingyu Ye, Dejian Xie, Wenlong Shen, Meijuan Yue, Qinpeng Jin, Xinjie Guo, Yan Zhang, Ping Li, Zhihu Zhao

{"title":"Dual control of liver regeneration by Nr1d1 homeostasis and Klf2 checkpoint.","authors":"Bingyu Ye, Dejian Xie, Wenlong Shen, Meijuan Yue, Qinpeng Jin, Xinjie Guo, Yan Zhang, Ping Li, Zhihu Zhao","doi":"10.1038/s41420-026-03039-5","DOIUrl":"https://doi.org/10.1038/s41420-026-03039-5","url":null,"abstract":"Following extensive liver resections, diminished liver regeneration impairs the maintenance or restoration of sufficient functional liver mass. Currently, effective therapies to restore liver regeneration are lacking, rendering liver transplantation the sole treatment option for end-stage liver disease. Therefore, it is imperative to elucidate the regulatory mechanisms underlying liver regeneration. In this study, we employed a multi-omics approach integrating Hi-C, RNA-seq, and ATAC-seq to dissect the early regulatory mechanisms of liver regeneration in rats and mice. Our results indicate that immune and inflammatory processes are markedly enriched during the early phase of regeneration, accompanied by upregulation of glucocorticoids (GCs) and their receptor (GR). First, the expression dynamics of the GC-related circadian gene Nr1d1 and its regulatory network-including Nfκbiα, Arntl, Clock, and Rora-align with chromatin reorganization, leading us to propose that the GC-GR-Nr1d1 axis is involved in maintaining liver homeostasis. Second, the GR-regulated FoxO family is significantly enriched, and the FoxO-associated gene Klf2 exhibits coordinated changes in expression, chromatin accessibility, and chromatin structure. Functional experiments demonstrate that Klf2 negatively regulates hepatocyte proliferation. Hence, we propose the GC-GR-FoxOs-Klf2 axis acts as a checkpoint in hepatocyte proliferation, preventing premature activation of proliferation- and cell cycle-related genes and ensuring orderly and efficient liver regeneration. Our findings on the role of GCs in liver regeneration may further support their future therapeutic application in liver diseases such as liver fibrosis, alcoholic cirrhosis, and hepatocellular carcinoma (HCC).","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":" ","pages":""},"PeriodicalIF":7.0,"publicationDate":"2026-04-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147670794","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}

引用次数: 0