Pub Date : 2025-12-23DOI: 10.1016/j.cell.2025.10.027
Matteo A. Molè, Sarah Elderkin, Irene Zorzan, Christopher Penfold, Nicole Horsley, Alexandra Pokhilko, Max Polanek, Andrea Palomar, Molika Sinha, Yang Wang, Alicia Quiñonero, Charalampos Androulidakis, Richard Acton, Kathryn Balmanno, Anneliese Jarman, Jhanavi Srinivasan, Adam Bendall, Sara Morales-Álvarez, Roberto Yagüe-Serrano, Katie Heywood, Stephen Harbottle, Mina Vasilic, Suzanne Cawood, Srividya Seshadri, Paul Serhal, Lauren Weavers, Ippokratis Sarris, Anastasia Mania, Rachel Gibbons, Lucy Laurier, Immaculada Sánchez-Ribas, Amparo Mercader, Pilar Alamá, Anthony Hoa Bui, Graham J. Burton, Tereza Cindrova-Davies, Ridma C. Fernando, Afshan McCarthy, Lusine Aghajanova, Liesl Nel-Themaat, Ruth B. Lathi, Simon J. Cook, Kathy K. Niakan, Alexander R. Dunn, Francisco Domínguez, Peter J. Rugg-Gunn
{"title":"Modeling human embryo implantation in vitro","authors":"Matteo A. Molè, Sarah Elderkin, Irene Zorzan, Christopher Penfold, Nicole Horsley, Alexandra Pokhilko, Max Polanek, Andrea Palomar, Molika Sinha, Yang Wang, Alicia Quiñonero, Charalampos Androulidakis, Richard Acton, Kathryn Balmanno, Anneliese Jarman, Jhanavi Srinivasan, Adam Bendall, Sara Morales-Álvarez, Roberto Yagüe-Serrano, Katie Heywood, Stephen Harbottle, Mina Vasilic, Suzanne Cawood, Srividya Seshadri, Paul Serhal, Lauren Weavers, Ippokratis Sarris, Anastasia Mania, Rachel Gibbons, Lucy Laurier, Immaculada Sánchez-Ribas, Amparo Mercader, Pilar Alamá, Anthony Hoa Bui, Graham J. Burton, Tereza Cindrova-Davies, Ridma C. Fernando, Afshan McCarthy, Lusine Aghajanova, Liesl Nel-Themaat, Ruth B. Lathi, Simon J. Cook, Kathy K. Niakan, Alexander R. Dunn, Francisco Domínguez, Peter J. Rugg-Gunn","doi":"10.1016/j.cell.2025.10.027","DOIUrl":"https://doi.org/10.1016/j.cell.2025.10.027","url":null,"abstract":"","PeriodicalId":9656,"journal":{"name":"Cell","volume":"26 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2025-12-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145823010","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}
Pub Date : 2025-12-22DOI: 10.1016/j.cell.2025.11.030
Zhengyuan Pang, Verina H. Leung, Cailynn C. Wang, Ahmadreza Attarpour, Anthony Rinaldi, Hanbing Shen, Maria Dolores Moya-Garzon, Logan H. Sigua, Claire Rammel, Alexandra Selke, Christopher Glynn, Melaina Yender, Senhan Xu, Javid J. Moslehi, Peng Wu, Jonathan Z. Long, Maged Goubran, Benjamin F. Cravatt, Li Ye
As our understanding of biological systems reaches single-cell and high spatial resolutions, it becomes imperative that pharmacological approaches match this precision to understand drug actions. This need is particularly urgent for the targeted covalent inhibitors that are currently re-entering the stage for cancer treatments. By leveraging the unique kinetics of click reactions, we developed volumetric clearing-assisted tissue click chemistry (vCATCH) to enable deep and homogeneous click labeling across the three-dimensional (3D) mammalian body. With simple and passive incubation steps, vCATCH offers cellular-resolution drug imaging in the entire adult mouse. We combined vCATCH with hydrogel-based reinforcement of three-dimensional imaging solvent-cleared organs (HYBRiD) imaging and virtual reality to visualize and quantify in vivo targets of two clinical cancer drugs, afatinib and ibrutinib, which recapitulated their known pharmacological distribution and revealed previously unreported tissue and cell-type engagement potentially linked to off-target effects. vCATCH provides a body-wide, unbiased platform to map covalent drug engagements at unprecedented scale and precision.
{"title":"Mapping cellular targets of covalent cancer drugs in the entire mammalian body","authors":"Zhengyuan Pang, Verina H. Leung, Cailynn C. Wang, Ahmadreza Attarpour, Anthony Rinaldi, Hanbing Shen, Maria Dolores Moya-Garzon, Logan H. Sigua, Claire Rammel, Alexandra Selke, Christopher Glynn, Melaina Yender, Senhan Xu, Javid J. Moslehi, Peng Wu, Jonathan Z. Long, Maged Goubran, Benjamin F. Cravatt, Li Ye","doi":"10.1016/j.cell.2025.11.030","DOIUrl":"https://doi.org/10.1016/j.cell.2025.11.030","url":null,"abstract":"As our understanding of biological systems reaches single-cell and high spatial resolutions, it becomes imperative that pharmacological approaches match this precision to understand drug actions. This need is particularly urgent for the targeted covalent inhibitors that are currently re-entering the stage for cancer treatments. By leveraging the unique kinetics of click reactions, we developed volumetric clearing-assisted tissue click chemistry (vCATCH) to enable deep and homogeneous click labeling across the three-dimensional (3D) mammalian body. With simple and passive incubation steps, vCATCH offers cellular-resolution drug imaging in the entire adult mouse. We combined vCATCH with hydrogel-based reinforcement of three-dimensional imaging solvent-cleared organs (HYBRiD) imaging and virtual reality to visualize and quantify <em>in vivo</em> targets of two clinical cancer drugs, afatinib and ibrutinib, which recapitulated their known pharmacological distribution and revealed previously unreported tissue and cell-type engagement potentially linked to off-target effects. vCATCH provides a body-wide, unbiased platform to map covalent drug engagements at unprecedented scale and precision.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"184 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2025-12-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145801470","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}
Pub Date : 2025-12-19DOI: 10.1016/j.cell.2025.11.027
Jessica Y. Huang, Michael Y. Gerner
Lymph nodes (LNs) enable innate defense to limit pathogen dissemination while also driving adaptive immunity. Yet, certain innate responses can restrict adaptive processes, suggesting that these must be tightly regulated. Here, we report that after infection or immunization, LN architecture is rapidly altered, with large-scale, polarized recruitment of neutrophils and monocytes from inflamed blood vessels and intranodal repositioning of natural killer (NK) cells. Mechanistically, dendritic cells (DCs) promote this through expression of inflammatory chemokines and integrin ligands. While these DC-driven innate responses are necessary for efficient pathogen containment, they paradoxically limit early adaptive immunity, with infiltrating neutrophils displacing lymphocytes and reducing the LN area available for T cell priming. Upon threat cessation, however, DCs and DC-recruited monocytes phagocytose the neutrophils, restoring tissue architecture and generating polarized domains for downstream adaptive immune cell activation. Thus, DCs orchestrate innate cell organization during inflammation, serving as rheostats of innate versus adaptive functions of the LN.
{"title":"Dendritic cells regulate the innate-adaptive balance in lymph nodes for optimal host defense","authors":"Jessica Y. Huang, Michael Y. Gerner","doi":"10.1016/j.cell.2025.11.027","DOIUrl":"https://doi.org/10.1016/j.cell.2025.11.027","url":null,"abstract":"Lymph nodes (LNs) enable innate defense to limit pathogen dissemination while also driving adaptive immunity. Yet, certain innate responses can restrict adaptive processes, suggesting that these must be tightly regulated. Here, we report that after infection or immunization, LN architecture is rapidly altered, with large-scale, polarized recruitment of neutrophils and monocytes from inflamed blood vessels and intranodal repositioning of natural killer (NK) cells. Mechanistically, dendritic cells (DCs) promote this through expression of inflammatory chemokines and integrin ligands. While these DC-driven innate responses are necessary for efficient pathogen containment, they paradoxically limit early adaptive immunity, with infiltrating neutrophils displacing lymphocytes and reducing the LN area available for T cell priming. Upon threat cessation, however, DCs and DC-recruited monocytes phagocytose the neutrophils, restoring tissue architecture and generating polarized domains for downstream adaptive immune cell activation. Thus, DCs orchestrate innate cell organization during inflammation, serving as rheostats of innate versus adaptive functions of the LN.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"47 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2025-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145777699","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}
Pub Date : 2025-12-19DOI: 10.1016/j.cell.2025.11.026
Min Kyung Shinn, Dylan T. Tomares, Vicky Liu, Avnika Pant, Yuanxin Qiu, Andreas Vitalis, You Jin Song, Yuna Ayala, Kiersten M. Ruff, Gregory W. Strout, Matthew D. Lew, Kannanganattu V. Prasanth, Rohit V. Pappu
{"title":"Nuclear speckle proteins form intrinsic and MALAT1-dependent microphases","authors":"Min Kyung Shinn, Dylan T. Tomares, Vicky Liu, Avnika Pant, Yuanxin Qiu, Andreas Vitalis, You Jin Song, Yuna Ayala, Kiersten M. Ruff, Gregory W. Strout, Matthew D. Lew, Kannanganattu V. Prasanth, Rohit V. Pappu","doi":"10.1016/j.cell.2025.11.026","DOIUrl":"https://doi.org/10.1016/j.cell.2025.11.026","url":null,"abstract":"","PeriodicalId":9656,"journal":{"name":"Cell","volume":"35 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2025-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145784806","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}
Pub Date : 2025-12-16DOI: 10.1016/j.cell.2025.11.024
Claire J. Millett, James J. Shaver, Bernadette Bracken, Sunny J. Jones, Robert J. Lovelett, Dave A. Rubinow, Rijul Singhal, Celia Charlton, Nadine Piazza, Quinn Hauck, Nikhil Sharma, Paul A. Muller
Enteric neurons (ENs) are interwoven into the gastrointestinal (GI) tract, where they integrate local and external information to coordinate gut function across diverse cell types. Since EN dysfunction underlies the pathophysiology of multiple GI diseases, targeting relevant EN populations presents a multifaceted therapeutic approach. Despite their importance in essential physiologies, ENs remain underexplored from a transcriptional, circuit-based, and functional perspective. To enable target identification and validation in drug discovery, we leveraged a suite of modern neuroscience tools and profiled ENs. Single-nuclei sequencing, chemogenetics, circuit tracing, and pharmacology resolved how EN populations can modulate GI motility, secretion, food intake, and inflammation. We then determined the extent of conservation between mouse and human EN subsets. This work provides disease-relevant insights into EN cell type- and region-specific functions, lays the methodological groundwork to further probe EN function in vivo, and highlights translational hurdles and opportunities between mouse and human.
{"title":"In vivo transcriptomic, functional, circuit-based, and translational analyses of enteric neurons","authors":"Claire J. Millett, James J. Shaver, Bernadette Bracken, Sunny J. Jones, Robert J. Lovelett, Dave A. Rubinow, Rijul Singhal, Celia Charlton, Nadine Piazza, Quinn Hauck, Nikhil Sharma, Paul A. Muller","doi":"10.1016/j.cell.2025.11.024","DOIUrl":"https://doi.org/10.1016/j.cell.2025.11.024","url":null,"abstract":"Enteric neurons (ENs) are interwoven into the gastrointestinal (GI) tract, where they integrate local and external information to coordinate gut function across diverse cell types. Since EN dysfunction underlies the pathophysiology of multiple GI diseases, targeting relevant EN populations presents a multifaceted therapeutic approach. Despite their importance in essential physiologies, ENs remain underexplored from a transcriptional, circuit-based, and functional perspective. To enable target identification and validation in drug discovery, we leveraged a suite of modern neuroscience tools and profiled ENs. Single-nuclei sequencing, chemogenetics, circuit tracing, and pharmacology resolved how EN populations can modulate GI motility, secretion, food intake, and inflammation. We then determined the extent of conservation between mouse and human EN subsets. This work provides disease-relevant insights into EN cell type- and region-specific functions, lays the methodological groundwork to further probe EN function <em>in vivo</em>, and highlights translational hurdles and opportunities between mouse and human.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"56 27 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2025-12-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145760282","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}
Pub Date : 2025-12-11Epub Date: 2025-10-24DOI: 10.1016/j.cell.2025.10.004
Tian Lu, Yuting Xie, Yingrui Wang, Xiling Lin, Xue Cai, Yuqi Zhang, Zongxiang Nie, Chang Su, Wanglong Gou, Hong Zhang, Jing Wang, Yan Zhong, Zeyin Lai, Jingjing Xiang, Peng-Fei Shan, Ju-Sheng Zheng, Huijun Wang, Yi Zhu, Tiannan Guo
Population aging is accelerating, yet the multi-organ aging process and the geroprotective effects of dietary protein restriction (PR) remain poorly understood. Here, we conducted comprehensive proteomic analyses on 41 mouse tissues during male mouse aging and PR. Our findings identified tissue-specific aging hallmarks, including widespread changes in immunoglobulins and serine protease inhibitors across multiple tissues. PR mitigated age-related tissue-specific protein expression, epigenomic states, and protein phosphorylation patterns, and it significantly improved adipose tissue functions. These findings were supported by independent reduced representation bisulfite sequencing (RRBS), phosphoproteomics, and pathological analyses. Furthermore, analysis of plasma samples from mice and humans confirmed the cardiovascular benefits of PR. We identified sexual and temporal variations in the impact of PR, with middle age being the optimal intervention period. Overall, our study depicts the multi-organ aging process and provides valuable insights into the geroprotective potential of PR.
{"title":"Protein restriction reprograms the multi-organ proteomic landscape of mouse aging.","authors":"Tian Lu, Yuting Xie, Yingrui Wang, Xiling Lin, Xue Cai, Yuqi Zhang, Zongxiang Nie, Chang Su, Wanglong Gou, Hong Zhang, Jing Wang, Yan Zhong, Zeyin Lai, Jingjing Xiang, Peng-Fei Shan, Ju-Sheng Zheng, Huijun Wang, Yi Zhu, Tiannan Guo","doi":"10.1016/j.cell.2025.10.004","DOIUrl":"10.1016/j.cell.2025.10.004","url":null,"abstract":"<p><p>Population aging is accelerating, yet the multi-organ aging process and the geroprotective effects of dietary protein restriction (PR) remain poorly understood. Here, we conducted comprehensive proteomic analyses on 41 mouse tissues during male mouse aging and PR. Our findings identified tissue-specific aging hallmarks, including widespread changes in immunoglobulins and serine protease inhibitors across multiple tissues. PR mitigated age-related tissue-specific protein expression, epigenomic states, and protein phosphorylation patterns, and it significantly improved adipose tissue functions. These findings were supported by independent reduced representation bisulfite sequencing (RRBS), phosphoproteomics, and pathological analyses. Furthermore, analysis of plasma samples from mice and humans confirmed the cardiovascular benefits of PR. We identified sexual and temporal variations in the impact of PR, with middle age being the optimal intervention period. Overall, our study depicts the multi-organ aging process and provides valuable insights into the geroprotective potential of PR.</p>","PeriodicalId":9656,"journal":{"name":"Cell","volume":" ","pages":"7309-7326.e20"},"PeriodicalIF":42.5,"publicationDate":"2025-12-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145370194","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}
Pub Date : 2025-12-11Epub Date: 2025-10-22DOI: 10.1016/j.cell.2025.09.022
Liming Yan, Yucen Huang, Yixiao Liu, Ji Ge, Shan Gao, Liping Tan, Lu Liu, Zhenyu Liu, Sihan Ye, Junbo Wang, Jiangran Xiong, Yu Zhou, Hesheng Zhao, Xiaoyue Zhao, Luke W Guddat, Yan Gao, Lan Zhu, Zihe Rao, Zhiyong Lou
In the SARS-CoV-2 replication-transcription complex (RTC), the nascent template-product duplex is unwound into a template strand for recycling and a product strand that needs to be capped. Here, we determined structures of the SARS-CoV-2 RTC in the pre- and post-capping initiation (CI) states. In the pre-CI state, the RTC has a dimer-of-dimeric architecture (ddRTC). The upstream RNA duplex in one RTC is reciprocally unwound by a helicase in a head-to-head-positioned RTC in the 3'-5' direction. The helicases bind either ADP or ADP⋅Pi in their ATP-binding pockets, suggesting a mechanism for ATP-hydrolysis-driven unwinding. In the post-CI state, the binding of nsp9 to the nsp12 nidovirus RdRp-associated nucleotidyltransferase (NiRAN) disrupts the ddRTC. The N terminus of nsp9 and the triphosphorylated 5' end of the product strand co-localize in NiRAN's catalytic site, exhibiting the state prior to nsp9 RNAylation for capping. These results provide an insight into the concurrence of template recycling and RNA capping in the SARS-CoV-2 RTC.
{"title":"Structural basis for the concurrence of template recycling and RNA capping in SARS-CoV-2.","authors":"Liming Yan, Yucen Huang, Yixiao Liu, Ji Ge, Shan Gao, Liping Tan, Lu Liu, Zhenyu Liu, Sihan Ye, Junbo Wang, Jiangran Xiong, Yu Zhou, Hesheng Zhao, Xiaoyue Zhao, Luke W Guddat, Yan Gao, Lan Zhu, Zihe Rao, Zhiyong Lou","doi":"10.1016/j.cell.2025.09.022","DOIUrl":"10.1016/j.cell.2025.09.022","url":null,"abstract":"<p><p>In the SARS-CoV-2 replication-transcription complex (RTC), the nascent template-product duplex is unwound into a template strand for recycling and a product strand that needs to be capped. Here, we determined structures of the SARS-CoV-2 RTC in the pre- and post-capping initiation (CI) states. In the pre-CI state, the RTC has a dimer-of-dimeric architecture (ddRTC). The upstream RNA duplex in one RTC is reciprocally unwound by a helicase in a head-to-head-positioned RTC in the 3'-5' direction. The helicases bind either ADP or ADP⋅P<sub>i</sub> in their ATP-binding pockets, suggesting a mechanism for ATP-hydrolysis-driven unwinding. In the post-CI state, the binding of nsp9 to the nsp12 nidovirus RdRp-associated nucleotidyltransferase (NiRAN) disrupts the ddRTC. The N terminus of nsp9 and the triphosphorylated 5' end of the product strand co-localize in NiRAN's catalytic site, exhibiting the state prior to nsp9 RNAylation for capping. These results provide an insight into the concurrence of template recycling and RNA capping in the SARS-CoV-2 RTC.</p>","PeriodicalId":9656,"journal":{"name":"Cell","volume":" ","pages":"7194-7205.e10"},"PeriodicalIF":42.5,"publicationDate":"2025-12-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145353975","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}
Pub Date : 2025-12-11Epub Date: 2025-10-24DOI: 10.1016/j.cell.2025.09.026
Lina Wang, Qiaoling Liu, Siru Li, Na Wang, Yan Chen, Junren Chen, Li Wang, Yuelin Huang, Zhen Sun, Ling Dong, Shao Li, Quentin Liu, Song Gao, Xiaochi Ma, Chengli Song, Qingkai Yang
Detection of DNA is a fundamental strategy for life to recognize non-self or abnormal-self to subsequently trigger the downstream responses. However, the mechanism underlying DNA sensing is incompletely understood. Here, we show that a key neural executioner, sterile alpha and Toll/interleukin-1 receptor (TIR) motif containing 1 (SARM1), senses double-stranded DNA (dsDNA) to promote cell death. dsDNA-bound and -activated SARM1 to degrade nicotinamide adenine dinucleotide (NAD+) in a sequence-independent manner. SARM1 bound dsDNA via the TIR domain, and lysine residues in the TIR domain contributed to dsDNA binding. In the cellular context, cytosolic dsDNA from dsDNA transfection or chemotherapy treatment was colocalized with SARM1 and activated SARM1 to elicit NAD+ degradation and cell death, which was abrogated by SARM1 knockout or DNA-binding residue mutation. Consistently, SARM1 knockout blocked chemotherapy-induced neuropathy (CIN) in mice. Our results reveal SARM1 as a DNA sensor, which might be targetable for therapeutic interventions.
{"title":"SARM1 senses dsDNA to promote NAD<sup>+</sup> degradation and cell death.","authors":"Lina Wang, Qiaoling Liu, Siru Li, Na Wang, Yan Chen, Junren Chen, Li Wang, Yuelin Huang, Zhen Sun, Ling Dong, Shao Li, Quentin Liu, Song Gao, Xiaochi Ma, Chengli Song, Qingkai Yang","doi":"10.1016/j.cell.2025.09.026","DOIUrl":"10.1016/j.cell.2025.09.026","url":null,"abstract":"<p><p>Detection of DNA is a fundamental strategy for life to recognize non-self or abnormal-self to subsequently trigger the downstream responses. However, the mechanism underlying DNA sensing is incompletely understood. Here, we show that a key neural executioner, sterile alpha and Toll/interleukin-1 receptor (TIR) motif containing 1 (SARM1), senses double-stranded DNA (dsDNA) to promote cell death. dsDNA-bound and -activated SARM1 to degrade nicotinamide adenine dinucleotide (NAD<sup>+</sup>) in a sequence-independent manner. SARM1 bound dsDNA via the TIR domain, and lysine residues in the TIR domain contributed to dsDNA binding. In the cellular context, cytosolic dsDNA from dsDNA transfection or chemotherapy treatment was colocalized with SARM1 and activated SARM1 to elicit NAD<sup>+</sup> degradation and cell death, which was abrogated by SARM1 knockout or DNA-binding residue mutation. Consistently, SARM1 knockout blocked chemotherapy-induced neuropathy (CIN) in mice. Our results reveal SARM1 as a DNA sensor, which might be targetable for therapeutic interventions.</p>","PeriodicalId":9656,"journal":{"name":"Cell","volume":" ","pages":"7137-7154.e21"},"PeriodicalIF":42.5,"publicationDate":"2025-12-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145370168","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}
Pub Date : 2025-12-11DOI: 10.1016/j.cell.2025.11.021
Sam Khan, Janice J.N. Li, Natasha B. Leighl
{"title":"Are ultrasensitive ctDNA assays ready for clinical use in early-stage NSCLC?","authors":"Sam Khan, Janice J.N. Li, Natasha B. Leighl","doi":"10.1016/j.cell.2025.11.021","DOIUrl":"https://doi.org/10.1016/j.cell.2025.11.021","url":null,"abstract":"","PeriodicalId":9656,"journal":{"name":"Cell","volume":"251 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2025-12-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145730703","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}
Pub Date : 2025-12-11DOI: 10.1016/j.cell.2025.11.001
Iván Ballesteros, Andrés Hidalgo
More than a century after their discovery, neutrophils continue to puzzle immunologists. Their remarkable migratory, cytotoxic, phagocytic, and degranulating capacities gave rise to the traditional perception that they are dedicated microbe hunters. Yet neutrophils possess an equally exceptional ability to acquire new traits across different environments, and when considered as a lineage collective, they are long-lived, reprogrammable, and retain memory of past insults. Here, we focus on the concept of the collective to make sense of both traditional properties and those that challenge existing dogmas. We model the structure of the collective as the combination of two biologically distinct compartments and discuss the unique properties that emerge beyond the sum of the individual cells. We hope that our review will stimulate discussion and spark new ideas about how neutrophils contribute to and can be exploited to promote health.
{"title":"The neutrophil collective","authors":"Iván Ballesteros, Andrés Hidalgo","doi":"10.1016/j.cell.2025.11.001","DOIUrl":"https://doi.org/10.1016/j.cell.2025.11.001","url":null,"abstract":"More than a century after their discovery, neutrophils continue to puzzle immunologists. Their remarkable migratory, cytotoxic, phagocytic, and degranulating capacities gave rise to the traditional perception that they are dedicated microbe hunters. Yet neutrophils possess an equally exceptional ability to acquire new traits across different environments, and when considered as a lineage collective, they are long-lived, reprogrammable, and retain memory of past insults. Here, we focus on the concept of the collective to make sense of both traditional properties and those that challenge existing dogmas. We model the structure of the collective as the combination of two biologically distinct compartments and discuss the unique properties that emerge beyond the sum of the individual cells. We hope that our review will stimulate discussion and spark new ideas about how neutrophils contribute to and can be exploited to promote health.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"1 1","pages":"7019-7035"},"PeriodicalIF":64.5,"publicationDate":"2025-12-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145732401","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}
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