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}
Cell-mediated drug-delivery systems have garnered significant attention for their potential to boost therapeutic efficacy in cancer treatment. Here, we engineered immunoglobulin E (IgE)-sensitized mast cells (IgE-MCs) to achieve antigen-guided delivery of oncolytic adenoviruses (OVs) and local immune activation. By harnessing tumor-specific antigens as allergens, IgE-MCs accumulated at antigen-positive tumors, enabling targeted OV delivery and releasing chemokines and inflammatory mediators that remodeled the tumor microenvironment. IgE-MCs encapsulating OVs induced robust anticancer immune responses and inhibited tumor growth in several murine models. Of note, in a humanized human epidermal growth factor receptor-2 (HER2)-positive patient-derived xenograft model, human MCs armed with anti-HER2 IgE and loaded with OVs increased intratumoral T cell responses and reduced tumor growth, demonstrating feasibility in a clinically relevant setting and supporting patient-specific IgE selection. Together, our study highlights the translational promise of IgE-MCs as an antigen-specific delivery platform for cancer immunotherapy.
{"title":"Sensitized mast cells for targeted drug delivery and augmented cancer immunotherapy","authors":"Yan Xu, Xiaoge Zhang, Xiao Han, Hanwei Huang, Chaoyang Meng, Yinxian Yang, Tao Sheng, En Ren, Jiaqi Shi, Kaixin He, Dong Cen, Peng Zhao, Weijia Fang, Hongjun Li, Yuqi Zhang, Xiujun Cai, Funan Liu, Jicheng Yu, Zhen Gu","doi":"10.1016/j.cell.2025.11.015","DOIUrl":"https://doi.org/10.1016/j.cell.2025.11.015","url":null,"abstract":"Cell-mediated drug-delivery systems have garnered significant attention for their potential to boost therapeutic efficacy in cancer treatment. Here, we engineered immunoglobulin E (IgE)-sensitized mast cells (IgE-MCs) to achieve antigen-guided delivery of oncolytic adenoviruses (OVs) and local immune activation. By harnessing tumor-specific antigens as allergens, IgE-MCs accumulated at antigen-positive tumors, enabling targeted OV delivery and releasing chemokines and inflammatory mediators that remodeled the tumor microenvironment. IgE-MCs encapsulating OVs induced robust anticancer immune responses and inhibited tumor growth in several murine models. Of note, in a humanized human epidermal growth factor receptor-2 (HER2)-positive patient-derived xenograft model, human MCs armed with anti-HER2 IgE and loaded with OVs increased intratumoral T cell responses and reduced tumor growth, demonstrating feasibility in a clinically relevant setting and supporting patient-specific IgE selection. Together, our study highlights the translational promise of IgE-MCs as an antigen-specific delivery platform for cancer immunotherapy.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"6 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2025-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145704285","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 : 2025-12-09DOI: 10.1016/j.cell.2025.11.016
Jeya Maria Jose Valanarasu, Hanwen Xu, Naoto Usuyama, Chanwoo Kim, Cliff Wong, Peniel Argaw, Racheli Ben Shimol, Angela Crabtree, Kevin Matlock, Alexandra Q. Bartlett, Jaspreet Bagga, Yu Gu, Sheng Zhang, Tristan Naumann, Bernard A. Fox, Bill Wright, Ari Robicsek, Brian Piening, Carlo Bifulco, Sheng Wang, Hoifung Poon
The tumor immune microenvironment (TIME) critically impacts cancer progression and immunotherapy response. Multiplex immunofluorescence (mIF) is a powerful imaging modality for deciphering TIME, but its applicability is limited by high cost and low throughput. We propose GigaTIME, a multimodal AI framework for population-scale TIME modeling by bridging cell morphology and states. GigaTIME learns a cross-modal translator to generate virtual mIF images from hematoxylin and eosin (H&E) slides by training on 40 million cells with paired H&E and mIF data across 21 proteins. We applied GigaTIME to 14,256 patients from 51 hospitals and over 1,000 clinics across seven US states in Providence Health, generating 299,376 virtual mIF slides spanning 24 cancer types and 306 subtypes. This virtual population uncovered 1,234 statistically significant associations linking proteins, biomarkers, staging, and survival. Such analyses were previously infeasible due to the scarcity of mIF data. Independent validation on 10,200 TCGA patients further corroborated our findings.
{"title":"Multimodal AI generates virtual population for tumor microenvironment modeling","authors":"Jeya Maria Jose Valanarasu, Hanwen Xu, Naoto Usuyama, Chanwoo Kim, Cliff Wong, Peniel Argaw, Racheli Ben Shimol, Angela Crabtree, Kevin Matlock, Alexandra Q. Bartlett, Jaspreet Bagga, Yu Gu, Sheng Zhang, Tristan Naumann, Bernard A. Fox, Bill Wright, Ari Robicsek, Brian Piening, Carlo Bifulco, Sheng Wang, Hoifung Poon","doi":"10.1016/j.cell.2025.11.016","DOIUrl":"https://doi.org/10.1016/j.cell.2025.11.016","url":null,"abstract":"The tumor immune microenvironment (TIME) critically impacts cancer progression and immunotherapy response. Multiplex immunofluorescence (mIF) is a powerful imaging modality for deciphering TIME, but its applicability is limited by high cost and low throughput. We propose <em>GigaTIME</em>, a multimodal AI framework for population-scale TIME modeling by bridging cell morphology and states. <em>GigaTIME</em> learns a cross-modal translator to generate virtual mIF images from hematoxylin and eosin (H&E) slides by training on 40 million cells with paired H&E and mIF data across 21 proteins. We applied <em>GigaTIME</em> to 14,256 patients from 51 hospitals and over 1,000 clinics across seven US states in Providence Health, generating 299,376 virtual mIF slides spanning 24 cancer types and 306 subtypes. This virtual population uncovered 1,234 statistically significant associations linking proteins, biomarkers, staging, and survival. Such analyses were previously infeasible due to the scarcity of mIF data. Independent validation on 10,200 TCGA patients further corroborated our findings.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"2 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2025-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145711128","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 : 2025-12-08DOI: 10.1016/j.cell.2025.11.011
Sung Ryul Choi, Thorsten B. Blum, Matteo Giono, Bibhas Roy, Ioannis Vakonakis, Dominic Schmid, Nicole Oelgarth, Apisha Ranganathan, Alvar D. Gossert, G.V. Shivashankar, Alfred Zippelius, Michel O. Steinmetz
Microtubules have long been recognized as upstream mediators of intracellular signaling, but the mechanisms underlying this fundamental function remain elusive. Here, we identify the structural basis by which microtubules regulate the guanine nucleotide exchange factor H1 (GEFH1), a key activator of the Ras homolog family member A (RhoA) pathway. We show that specific features of the microtubule lattice bind the C1 domain of GEFH1, leading to the sequestration and inactivation of this signaling protein. Targeted mutations in C1 residues disrupt this interaction, triggering GEFH1 release and activation of RhoA-dependent immune responses. Building on this sequestration-and-release mechanism, we identify microtubule-binding C1 domains in additional signaling proteins, including other guanine nucleotide exchange factors (GEFs), kinases, a GTPase-activating protein (GAP), and a tumor suppressor, and show that microtubule-mediated regulation via C1 domains is conserved in the Ras association domain-containing protein 1A (RASSF1A). Our findings establish a structural framework for understanding how microtubules can function as spatiotemporal signal sensors, integrating and processing diverse signaling pathways to control important cellular processes.
{"title":"Structural basis of microtubule-mediated signal transduction","authors":"Sung Ryul Choi, Thorsten B. Blum, Matteo Giono, Bibhas Roy, Ioannis Vakonakis, Dominic Schmid, Nicole Oelgarth, Apisha Ranganathan, Alvar D. Gossert, G.V. Shivashankar, Alfred Zippelius, Michel O. Steinmetz","doi":"10.1016/j.cell.2025.11.011","DOIUrl":"https://doi.org/10.1016/j.cell.2025.11.011","url":null,"abstract":"Microtubules have long been recognized as upstream mediators of intracellular signaling, but the mechanisms underlying this fundamental function remain elusive. Here, we identify the structural basis by which microtubules regulate the guanine nucleotide exchange factor H1 (GEFH1), a key activator of the Ras homolog family member A (RhoA) pathway. We show that specific features of the microtubule lattice bind the C1 domain of GEFH1, leading to the sequestration and inactivation of this signaling protein. Targeted mutations in C1 residues disrupt this interaction, triggering GEFH1 release and activation of RhoA-dependent immune responses. Building on this sequestration-and-release mechanism, we identify microtubule-binding C1 domains in additional signaling proteins, including other guanine nucleotide exchange factors (GEFs), kinases, a GTPase-activating protein (GAP), and a tumor suppressor, and show that microtubule-mediated regulation via C1 domains is conserved in the Ras association domain-containing protein 1A (RASSF1A). Our findings establish a structural framework for understanding how microtubules can function as spatiotemporal signal sensors, integrating and processing diverse signaling pathways to control important cellular processes.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"138 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2025-12-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145704286","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 : 2025-12-05DOI: 10.1016/j.cell.2025.11.009
Quan Jiang, Ling-Xiao Shao, Shenqin Yao, Neil K. Savalia, Amelia D. Gilbert, Pasha A. Davoudian, Jack D. Nothnagel, Guilian Tian, Tin Shing Hung, Hei Ming Lai, Kevin T. Beier, Hongkui Zeng, Alex C. Kwan
Psilocybin holds promise as a treatment for mental illnesses. One dose of psilocybin induces structural remodeling of dendritic spines in the medial frontal cortex in mice. The dendritic spines would be innervated by presynaptic neurons, but the sources of these inputs have not been identified. Here, using monosynaptic rabies tracing, we map the brain-wide distribution of inputs to frontal cortical pyramidal neurons. We discover that psilocybin's effect on connectivity is network specific, strengthening the routing of inputs from perceptual and medial regions (homolog of the default mode network) to subcortical targets while weakening inputs that are part of cortico-cortical recurrent loops. The pattern of synaptic reorganization depends on the drug-evoked spiking activity because silencing a presynaptic region during psilocybin administration disrupts the rewiring. Collectively, the results reveal the impact of psilocybin on the connectivity of large-scale cortical networks and demonstrate neural activity modulation as an approach to sculpt the psychedelic-evoked neural plasticity.
{"title":"Psilocybin triggers an activity-dependent rewiring of large-scale cortical networks","authors":"Quan Jiang, Ling-Xiao Shao, Shenqin Yao, Neil K. Savalia, Amelia D. Gilbert, Pasha A. Davoudian, Jack D. Nothnagel, Guilian Tian, Tin Shing Hung, Hei Ming Lai, Kevin T. Beier, Hongkui Zeng, Alex C. Kwan","doi":"10.1016/j.cell.2025.11.009","DOIUrl":"https://doi.org/10.1016/j.cell.2025.11.009","url":null,"abstract":"Psilocybin holds promise as a treatment for mental illnesses. One dose of psilocybin induces structural remodeling of dendritic spines in the medial frontal cortex in mice. The dendritic spines would be innervated by presynaptic neurons, but the sources of these inputs have not been identified. Here, using monosynaptic rabies tracing, we map the brain-wide distribution of inputs to frontal cortical pyramidal neurons. We discover that psilocybin's effect on connectivity is network specific, strengthening the routing of inputs from perceptual and medial regions (homolog of the default mode network) to subcortical targets while weakening inputs that are part of cortico-cortical recurrent loops. The pattern of synaptic reorganization depends on the drug-evoked spiking activity because silencing a presynaptic region during psilocybin administration disrupts the rewiring. Collectively, the results reveal the impact of psilocybin on the connectivity of large-scale cortical networks and demonstrate neural activity modulation as an approach to sculpt the psychedelic-evoked neural plasticity.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"2 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2025-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145689948","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 : 2025-12-04DOI: 10.1016/j.cell.2025.11.014
Svenja M. Lorenz, Adam Wahida, Mark J. Bostock, Tobias Seibt, André Santos Dias Mourão, Anastasia Levkina, Dietrich Trümbach, Mohamed Soudy, David Emler, Nicola Rothammer, Marcel S. Woo, Jana K. Sonner, Mariia Novikova, Bernhard Henkelmann, Maceler Aldrovandi, Daniel F. Kaemena, Eikan Mishima, Perrine Vermonden, Zhi Zong, Deng Cheng, Marcus Conrad
Ferroptosis, driven by uncontrolled peroxidation of membrane phospholipids, is distinct from other cell death modalities because it lacks an initiating signal and is surveilled by endogenous antioxidant defenses. Glutathione peroxidase 4 (GPX4) is the guardian of ferroptosis, although its membrane-protective function remains poorly understood. Here, structural and functional analyses of a missense mutation in GPX4 (p.R152H), which causes early-onset neurodegeneration, revealed that this variant disrupts membrane anchoring without considerably impairing its catalytic activity. Spatiotemporal Gpx4 deletion or neuron-specific GPX4R152H expression in mice induced degeneration of cortical and cerebellar neurons, accompanied by progressive neuroinflammation. Patient induced pluripotent stem cell (iPSC)-derived cortical neurons and forebrain organoids displayed increased ferroptotic vulnerability, mirroring key pathological features, and were sensitive to ferroptosis inhibition. Neuroproteomics revealed Alzheimer’s-like signatures in affected brains. These findings highlight the necessity of proper GPX4 membrane anchoring, establish ferroptosis as a key driver of neurodegeneration, and provide the rationale for targeting ferroptosis as a therapeutic strategy in neurodegenerative disease.
{"title":"A fin-loop-like structure in GPX4 underlies neuroprotection from ferroptosis","authors":"Svenja M. Lorenz, Adam Wahida, Mark J. Bostock, Tobias Seibt, André Santos Dias Mourão, Anastasia Levkina, Dietrich Trümbach, Mohamed Soudy, David Emler, Nicola Rothammer, Marcel S. Woo, Jana K. Sonner, Mariia Novikova, Bernhard Henkelmann, Maceler Aldrovandi, Daniel F. Kaemena, Eikan Mishima, Perrine Vermonden, Zhi Zong, Deng Cheng, Marcus Conrad","doi":"10.1016/j.cell.2025.11.014","DOIUrl":"https://doi.org/10.1016/j.cell.2025.11.014","url":null,"abstract":"Ferroptosis, driven by uncontrolled peroxidation of membrane phospholipids, is distinct from other cell death modalities because it lacks an initiating signal and is surveilled by endogenous antioxidant defenses. Glutathione peroxidase 4 (GPX4) is the guardian of ferroptosis, although its membrane-protective function remains poorly understood. Here, structural and functional analyses of a missense mutation in GPX4 (p.R152H), which causes early-onset neurodegeneration, revealed that this variant disrupts membrane anchoring without considerably impairing its catalytic activity. Spatiotemporal <em>Gpx4</em> deletion or neuron-specific GPX4<sup>R152H</sup> expression in mice induced degeneration of cortical and cerebellar neurons, accompanied by progressive neuroinflammation. Patient induced pluripotent stem cell (iPSC)-derived cortical neurons and forebrain organoids displayed increased ferroptotic vulnerability, mirroring key pathological features, and were sensitive to ferroptosis inhibition. Neuroproteomics revealed Alzheimer’s-like signatures in affected brains. These findings highlight the necessity of proper GPX4 membrane anchoring, establish ferroptosis as a key driver of neurodegeneration, and provide the rationale for targeting ferroptosis as a therapeutic strategy in neurodegenerative disease.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"1 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2025-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145673657","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 : 2025-12-04DOI: 10.1016/j.cell.2025.11.013
Rose Z. Hill, Jonathan W. Nelson, Georgina Gyarmati, Silvia Medrano, Sepenta Shirvan, James A. McCormick, Sebastian Burquez, Jeanine Ahmed, Diana G. Eng, Jan Wysocki, Adrienne E. Dubin, M. Rocio Servin-Vences, Arjun Lakshmanan, R. Ariel Gomez, Maria Luisa S. Sequeira-Lopez, Stuart J. Shankland, Daniel Batlle, Jeffrey H. Miner, Janos Peti-Peterdi, Ardem Patapoutian
Renin synthesis and release is the rate-limiting step of the renin-angiotensin-aldosterone system (RAAS) that controls fluid homeostasis. A major activator of the RAAS is a decrease in perfusion pressure within the kidneys, suggesting a link between renal mechanotransduction and renin. However, the identity of the mechanosensor(s) in the kidneys and their physiological significance to the RAAS remain unclear. We find that loss of the force-gated nonselective cation channel PIEZO2 in cells of renin lineage dysregulates the RAAS by elevating renin. We observe that PIEZO2 is expressed in renin-producing juxtaglomerular granular cells and is required for their calcium dynamics in vivo. PIEZO2 deficiency in cells of renin lineage drives renin-dependent and MAS-receptor-dependent glomerular hyperfiltration and regulates the RAAS during acute and chronic blood volume challenges. Collectively, our study identifies PIEZO2 as an essential regulator of juxtaglomerular granular cell calcium activity and renin in vivo.
{"title":"Renal PIEZO2 is an essential regulator of renin","authors":"Rose Z. Hill, Jonathan W. Nelson, Georgina Gyarmati, Silvia Medrano, Sepenta Shirvan, James A. McCormick, Sebastian Burquez, Jeanine Ahmed, Diana G. Eng, Jan Wysocki, Adrienne E. Dubin, M. Rocio Servin-Vences, Arjun Lakshmanan, R. Ariel Gomez, Maria Luisa S. Sequeira-Lopez, Stuart J. Shankland, Daniel Batlle, Jeffrey H. Miner, Janos Peti-Peterdi, Ardem Patapoutian","doi":"10.1016/j.cell.2025.11.013","DOIUrl":"https://doi.org/10.1016/j.cell.2025.11.013","url":null,"abstract":"Renin synthesis and release is the rate-limiting step of the renin-angiotensin-aldosterone system (RAAS) that controls fluid homeostasis. A major activator of the RAAS is a decrease in perfusion pressure within the kidneys, suggesting a link between renal mechanotransduction and renin. However, the identity of the mechanosensor(s) in the kidneys and their physiological significance to the RAAS remain unclear. We find that loss of the force-gated nonselective cation channel PIEZO2 in cells of renin lineage dysregulates the RAAS by elevating renin. We observe that PIEZO2 is expressed in renin-producing juxtaglomerular granular cells and is required for their calcium dynamics <em>in vivo</em>. PIEZO2 deficiency in cells of renin lineage drives renin-dependent and MAS-receptor-dependent glomerular hyperfiltration and regulates the RAAS during acute and chronic blood volume challenges. Collectively, our study identifies PIEZO2 as an essential regulator of juxtaglomerular granular cell calcium activity and renin <em>in vivo</em>.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"28 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2025-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145673658","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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