Cell最新文献

{"title":"Ferroptosis inhibition enhances liver and lung graft function.","authors":"Geraldine Veeckmans, Lene Devos, Nicholas Gilbo, Dieter Van Beersel, Camilla Scarpellini, Joris Blondeel, Magali Walravens, Greta Klejborowska, Caroline Lanthier, Michele Wölk, Sebastian Müller, Christine Gaillet, Ludovic Colombeau, Behrouz Hassannia, Matthias Längin, Martin Bender, Jan-Michael Abicht, Bruno Reichart, Hans De Winter, Maria Fedorova, Raphaël Rodriguez, Jacques Pirenne, Laurens J Ceulemans, Ina Jochmans, Koen Augustyns, Diethard Monbaliu, Arne Neyrinck, Tom Vanden Berghe","doi":"10.1016/j.cell.2026.04.024","DOIUrl":"https://doi.org/10.1016/j.cell.2026.04.024","url":null,"abstract":"<p><p>Ischemia-reperfusion injury (IRI) is a major clinical challenge in transplantation, vascular surgeries, myocardial infarction, and stroke. Disruption of energy and redox homeostasis triggers ferroptosis, a regulated, iron-dependent form of cell death, leading to organ dysfunction. We identify an early and transient increase of lipid peroxidation in human liver transplants and validate it as a therapeutic target. FXT-001, a ferroptosis inhibitor with dual radical and iron-trapping activity, provides robust protection in preclinical models, including ex situ perfusion of porcine liver and lung grafts. In a split ex vivo machine perfusion setting using declined human donors, FXT-001 treatment preserves graft viability, whereas untreated lungs deteriorate. We also develop FXT-002 and FXT-003 with enhanced pharmacokinetic and safety profiles. These findings support the use of ferroptosis inhibitors as a therapeutic strategy in transplantation and other IRI-associated conditions.</p>","PeriodicalId":9656,"journal":{"name":"Cell","volume":" ","pages":""},"PeriodicalIF":42.5,"publicationDate":"2026-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147863545","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The rise of polyploids during environmental upheaval.","authors":"Hengchi Chen, Fabricio Almeida-Silva, Garben Logghe, Steven Maere, Dries Bonte, Yves Van de Peer","doi":"10.1016/j.cell.2026.04.008","DOIUrl":"https://doi.org/10.1016/j.cell.2026.04.008","url":null,"abstract":"<p><p>Polyploidy, or whole-genome duplication (WGD), serves as both a significant evolutionary force and a potential evolutionary dead end, particularly among angiosperms. Despite the prevalence of polyploid organisms, instances of ancient polyploidy are surprisingly rare, presenting a paradox that remains poorly understood. In this study, we constructed a comprehensive genomic dataset of 470 angiosperm species and dated 132 ancient WGD events that are non-randomly distributed, revealing a clustering around pivotal periods of environmental upheaval and extinction. Notably, our findings highlight a strong correlation between waves of paleopolyploidization and significant events such as the Middle Miocene Disruption, the Eocene-Oligocene Transition (EOT), the Paleocene-Eocene Thermal Maximum (PETM), the Cretaceous-Paleogene (K-Pg) extinction, and different oceanic anoxic events (OAEs). We propose that polyploid organisms have an increased chance of survival during times of great environmental turmoil, a conclusion with important implications in the context of contemporary climate change and rapid global warming.</p>","PeriodicalId":9656,"journal":{"name":"Cell","volume":" ","pages":""},"PeriodicalIF":42.5,"publicationDate":"2026-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147863589","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Multimodal clocks of human aging.","authors":"Jiaming Li, Beier Jiang, Wei Zhang, Junwei Hao, Zhili Liu, Qianzhao Ji, Yandong Zheng, Xiaoyong Lu, Zikai Zheng, Shuai Ma, Yanlin Fan, Dan-Dan Gao, Xiao-Wen Hou, Jing Li, Jiazhen Tang, Yaobin Jing, Lingling Geng, Ruochen Wu, Baohu Zhang, Shuhui Sun, Yusheng Cai, Kaowen Yan, Muzhao Xiong, Chen Dong, Xibo Ma, Gang Xu, Zhejun Ji, Haoteng Yan, Quan Zheng, Honghao Huang, Li Zhang, Junming Li, Mengmeng Jiang, Liu-Jun Xu, Yifan Chen, Geyue Qu, Wan Lei, Hengchao Wang, Jun Ping, Jia Zhou, Ming Yi, Mingjin Jiang, Ying Jing, Wei-Dong Ye, Xiao Zhang, Xi Chu, Yuting He, Qian Zhao, Qi Wu, Meiling He, Lina Ma, Peng Liu, Liyun Zhao, Qiao-Cheng Zhai, Jun Qin, Jie Lu, Xianhe Yang, Shuo Zhang, Yu Xiong, Hua Ren, Wei Yang, Zhanmei Huang, Jiachen Zhang, Min Zhang, Pei Chen, Jian Dong, Yu Zhang, Tingting Yan, Jin-Lin Ye, Ping Huang, Zhigang Qi, Yong Liu, Jichen Shuai, Cheng-Shui Chen, Ping Li, Dawei Li, Xiuhua Xu, Xuexian Song, Jingyi Li, Jiale Ping, Jinghao Hu, Xiaoyan Sun, Jiaqi Ai, Zhengqin Wang, Yuxin Zhang, Peng Yang, Taixin Ning, Yan Yu, Zan He, Hui Zhang, Tianyang Zhang, Yuanhan Yang, Qiaoran Wang, Fangmin Lin, Xiangmei Jin, Xuewei Chen, Jie Ren, Moshi Song, Si Wang, Jiayin Yang, Jianming Li, Weihong Song, Fuchu He, Yun-Gui Yang, Gang Pei, Jing Qu, Wei Zhang, Jun Pu, Feng Zhang, Guoguang Zhao, Weiqi Zhang, Guang-Hui Liu","doi":"10.1016/j.cell.2026.04.025","DOIUrl":"https://doi.org/10.1016/j.cell.2026.04.025","url":null,"abstract":"<p><p>Human aging is characterized by complex structural and functional decline, but quantifying its heterogeneity and assessing biological age remain challenges. We present the mCAS (multicentric Chinese aging standardized cohort) developed from 2,019 Chinese individuals aged 18-91 years. Integrating high-dimensional clinical, physiological, and molecular-level data, we constructed a three-tiered aging framework: the core capacity clock (CC-clock) to quantify clinical physiological decline, the multimodal clock (MM-clock) with extensive parameter coverage and enhanced predictive precision, and organ-associated aging clocks. Cross-layer analysis demonstrates that plasma protein clocks not only capture chronological age but also serve as efficient proxies for systemic physiological capacity. Leveraging this framework for discovery, we identified the age-dependent accumulation of coagulation factors as a driver of multi-organ senescence and systemic inflammatory activation. This study provides a foundational framework that bridges molecular signatures with functional decline, identifies new biomarkers for aging assessment, and reveals a novel translational driver of aging.</p>","PeriodicalId":9656,"journal":{"name":"Cell","volume":" ","pages":""},"PeriodicalIF":42.5,"publicationDate":"2026-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147863580","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Genetic basis of phytoalexin-mediated chemical defense in plants.","authors":"Zhanli Wang, Lu Han, Lei Gao, Liyun Zhang, Yan Xie, Hanwu Liu, Junping Fan, Ming Wu, Ning Yue, Yan Wang, Meng Han, Tongcan Sun, Qi Ding, Xiyin Zheng, Jidong Cao, Xueqi Shen, Haijun Wang, Tuxunaili Aizitili, Chunyan Wu, Xuehong Wu, Zhenhua Liu, Yiguo Hong, Xiaoguang Lei, Yule Liu","doi":"10.1016/j.cell.2026.04.021","DOIUrl":"https://doi.org/10.1016/j.cell.2026.04.021","url":null,"abstract":"<p><p>Phytoalexins are core components of plant chemical defense against pathogens. However, the genetic basis and regulatory mechanisms governing their biosynthesis remain preliminary. Debneyol is a well-defined, broad-spectrum fungicidal phytoalexin. Here, we elucidate its biosynthetic pathway, key regulators, and activity against multiple pathogens. We show that debneyol is synthesized from farnesyl pyrophosphate (FPP) through three steps catalyzed by 5-epi-aristolochene synthase (EAS), 5-epi-aristolochene epoxidase (EAE), and epoxide hydrolase-1 (EH1). MCD1 (miR1919-targeted cell death-factor-1) interacts with EAS and EAE, enhancing their association and EAE activity and promoting debneyol biosynthesis. Increased MCD1 expression confers plant resistance not only against fungal but also viral and bacterial pathogens. Our work reveals a complete plant phytoalexin-based chemical defense machinery, opening avenues for engineering broad-spectrum plant resistance and industrial-scale debneyol production via synthetic biology.</p>","PeriodicalId":9656,"journal":{"name":"Cell","volume":" ","pages":""},"PeriodicalIF":42.5,"publicationDate":"2026-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147863559","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"AI-predicted spatial transcriptomics unlocks breast cancer biomarkers from pathology.","authors":"Eldad D Shulman, Emma M Campagnolo, Roshan Lodha, Youngmin Chung, Amos Stemmer, Thomas Cantore, Beibei Ru, Tian-Gen Chang, Sumona Biswas, Saugato Rahman Dhruba, Sumeet Patiyal, Sushant Patkar, Andrew Wang, Ranjan K Barman, Chuhan Wang, Rohit Paul, Sarath Chandra Kalisetty, Tom Hu, MacLean P Nasrallah, Ellis Patrick, Jean Yang, Yuan Yuan, Karine Sargsyan, Amy Plotkin, Padma Sheila Rajagopal, Stephen-John Sammut, Stanley Lipkowitz, Peng Jiang, Carlos Caldas, Simon R V Knott, Kenneth Aldape, Joo Sang Lee, Danh-Tai Hoang, Eytan Ruppin","doi":"10.1016/j.cell.2026.04.023","DOIUrl":"https://doi.org/10.1016/j.cell.2026.04.023","url":null,"abstract":"<p><p>Spatial transcriptomics (ST) assays are transforming our understanding of tumor heterogeneity, but their high cost limits their application in large-scale biomarker discovery. Here, we present \"Path2Space,\" a deep-learning model that predicts spatial gene expression directly from histopathology slides. Trained on extensive breast cancer ST data, Path2Space robustly predicts the spatial expression of thousands of genes, outperforming 21 established methods. Charting the tumor microenvironment (TME) of 976 breast cancer TCGA (The Cancer Genome Atlas) tumors, it accurately infers cell-type abundances and identifies three spatially defined breast cancer subgroups with distinct survival outcomes. Notably, the derived low-cost spatial TME landscapes enable more accurate predictions of patient response to chemotherapy and trastuzumab compared with costly conventional bulk-sequencing-based biomarkers. Path2Space thus offers a scalable, fast, and cost-effective alternative to molecular assays. It opens avenues for large cohort treatment biomarker discovery and translationally relevant insights into tumor biology, with potential applicability across many cancer indications.</p>","PeriodicalId":9656,"journal":{"name":"Cell","volume":" ","pages":""},"PeriodicalIF":42.5,"publicationDate":"2026-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147863524","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Streptomyces enrichment in roots during drought is uncoupled from plant benefit and is driven by host suppression of iron uptake and immunity.","authors":"Connor R Fitzpatrick, Ryker Allen Smith, Junko Hige, Theresa F Law, Dor Russ, Oluwadamilola Elizabeth Ajayi, Abdul Aziz Eida, Pierre Jacob, Monet Jowers, Narender Kumar, Cindy Thao Uyen Lai, Manuel Anguita-Maeso, S Brook Peterson, Chinmay Saha, Tara Skelly, Qinqin Zhao, Wenbin Zhou, Sarah R Grant, Joseph D Mougous, Corbin D Jones, Jeffery L Dangl","doi":"10.1016/j.cell.2026.04.027","DOIUrl":"https://doi.org/10.1016/j.cell.2026.04.027","url":null,"abstract":"<p><p>Drought reshapes the plant root microbiota, yet the mechanistic drivers and consequences of this observation remain unclear. We discovered that suppression of host immunity and iron homeostasis is required for Streptomyces enrichment in roots during drought across diverse soils. Genetic and physiological manipulation of these host pathways confirmed their requirement in modulating Streptomyces root enrichment. Drought-induced suppression of iron uptake was conserved across the ∼160 mya monocot-eudicot divergence. Some Streptomyces strains enhanced plant growth and rescued iron uptake under drought. These benefits were uncoupled from Streptomyces root enrichment. They were instead shaped by intra-Streptomyces antagonism. We propose a two-step model: drought-driven downregulation of host iron and immune pathways enriches Streptomyces, while intra-genus dynamics fine-tune strain-level assembly and functional outcomes. Our data refine the idea that Streptomyces are enriched in roots during drought in response to a plant \"cry for help\" and consequently contribute to the alleviation of this abiotic stress.</p>","PeriodicalId":9656,"journal":{"name":"Cell","volume":" ","pages":""},"PeriodicalIF":42.5,"publicationDate":"2026-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147863581","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Fronto-insular circuit mechanisms of accelerated intermittent theta burst stimulation.","authors":"Shane B Johnson, Devin Rocks, Laura Chalençon, Kenneth Johnson, Umair Hassan, Anisul Arefin, Gülcan Akgül, Alexander Donatelle, Henry Asher, Immanuel Elbau, David Estrin, Rebecca Zhang, Alexandra Lenz, Rachel Mikofsky, Cory Knox, Rachael Han, Pooja Suganthan, Tahrima Chowdhury, Christine Kuang, Daniel Shaver, Parsa Nilchian, Puja Parekh, Jacob Roshgadol, Natalia DeMarco Garcia, Matthew Wright, Lindsay Victoria, Benjamin Zebley, Joshua Levitz, Corey J Keller, Aaron D Boes, Conor Liston","doi":"10.1016/j.cell.2026.04.030","DOIUrl":"https://doi.org/10.1016/j.cell.2026.04.030","url":null,"abstract":"<p><p>Transcranial magnetic stimulation (TMS) is a widely used neuromodulation treatment for depression, but its mechanisms are poorly understood. Indirect clinical evidence suggests that TMS enhances plasticity within the prefrontal cortical target site and engages downstream networks. However, establishing causal mechanisms to help optimize the large stimulation parameter space has been challenging. Using an optogenetic model of accelerated intermittent theta burst stimulation (prelimbic [PL]-aiTBS) that drives rapid antidepressant-like effects, we examined cell type-specific effects on synapse-related gene expression, increased spine density, and increased excitatory currents in prefrontal intratelencephalic projection neurons. Whole-brain c-Fos immunolabeling, fiber photometry, chemogenetic, and projection-specific optogenetic manipulations revealed that PL-aiTBS activates a fronto-insular network that is necessary and sufficient for its antidepressant-like behavioral effects. Finally, we validate a key role for fronto-insular connectivity and TMS-evoked responses in the human insula using intracortical stereo-electroencephalogram (EEG) and resting-state fMRI. These results establish a fronto-insular circuit as a critical mediator of the antidepressant effects of aiTBS.</p>","PeriodicalId":9656,"journal":{"name":"Cell","volume":" ","pages":""},"PeriodicalIF":42.5,"publicationDate":"2026-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147855976","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A blood-brain barrier-like vascular gate limits immunotherapy efficacy in neuroendocrine cancers.","authors":"Yiyun Wang, Ailing Zhong, Bo Wang, Xiaoqian Zhai, Chang Lei, Zuoyu Liang, Xintong Deng, Jian Zhong, Chaoxin Xiao, Jianan Zheng, Baohong Wu, Lanxin Zhang, Yuying Wang, Xiangmeng Luo, Jian Wang, Mengsha Zhang, Hongyu Liu, Xudong Wan, Siqi Dai, Yucen Yang, Shiyu Zhang, Weiya Wang, Shengyong Yang, Jianxin Xue, Chengjian Zhao, Tuomas Tammela, Zhiming Li, Yan Zhang, Feifei Na, Manli Wang, Yu Liu, Chong Chen","doi":"10.1016/j.cell.2026.04.017","DOIUrl":"https://doi.org/10.1016/j.cell.2026.04.017","url":null,"abstract":"<p><p>Small cell lung cancer (SCLC), a highly aggressive neuroendocrine malignancy, exhibits poor response to immunotherapy, and the underlying mechanisms remain unclear. Here, we identify a blood-brain barrier-like vascular gate (BVG) in SCLC, distinct from non-SCLC (NSCLC) and other cancers, composed of tightly connected endothelial cells, a thickened basement membrane, and dense pericyte coverage. Functionally, this blood-brain barrier-like vascular gate restricts immune cell infiltration, contributing to SCLC's immunotherapy resistance. Mechanistically, achaete-scute family basic-helix-loop-helix (bHLH) transcription factor 1 (ASCL1), the master transcription factor of SCLC, is essential for BVG formation by regulating insulin-like growth factor-binding protein 5 (IGFBP5), which activates the IGF1 signaling in endothelial cells. IGFBP5 knockout or treatment with the IGF1R inhibitor OSI-906 enhances CD8⁺ T cell infiltration and synergizes with anti-PD1 therapy. Furthermore, this ASCL1-IGFBP5-IGF1R axis and the BVG are conserved across multiple neuroendocrine cancers (NECs). Our findings reveal a previously unrecognized vascular gate in NECs and propose novel therapeutic strategies to enhance immunotherapy efficacy in these recalcitrant cancers.</p>","PeriodicalId":9656,"journal":{"name":"Cell","volume":" ","pages":""},"PeriodicalIF":42.5,"publicationDate":"2026-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147855983","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A cell type-specific mechanism driving the rapid antidepressant effects of transcranial magnetic stimulation.","authors":"Michael W Gongwer, Alex Qi, Alexander S Enos, Sophia A Rueda Mora, Sabahaddin Taha Solakoğlu, Russell N Ahmed, Cassandra B Klune, Meelan Shari, Adrienne Q Kashay, Owen H Williams, Aliza Hacking, Jack P Riley, Gary A Wilke, Yihong Yang, Hanbing Lu, Andrew F Leuchter, Laura A DeNardo, Scott A Wilke","doi":"10.1016/j.cell.2025.12.040","DOIUrl":"https://doi.org/10.1016/j.cell.2025.12.040","url":null,"abstract":"<p><p>Repetitive transcranial magnetic stimulation (rTMS) is an emerging treatment for brain disorders, but its therapeutic mechanism is poorly understood. We developed a mouse model of rTMS with superior clinical face validity and investigated the neural mechanism by which accelerated intermittent theta burst stimulation (aiTBS), the first rapid-acting rTMS antidepressant protocol, reversed chronic stress-induced behavioral deficits. Using fiber photometry, we showed that aiTBS drives distinct patterns of neural activity in intratelencephalic (IT) and pyramidal tract (PT) projection neurons in dorsomedial prefrontal cortex (dmPFC). However, only IT neurons exhibited persistently increased activity during both aiTBS and subsequent depression-related behaviors. aiTBS reversed stress-related loss of dendritic spines on IT, but not PT neurons, further demonstrating cell type-specific effects of stimulation. Chemogenetically inhibiting dmPFC IT, but not PT neurons, during rTMS blocked the antidepressant-like behavioral effects of aiTBS. Thus, we demonstrate a prefrontal mechanism linking rapid aiTBS-driven therapeutic effects to cell type-specific circuit plasticity.</p>","PeriodicalId":9656,"journal":{"name":"Cell","volume":" ","pages":""},"PeriodicalIF":42.5,"publicationDate":"2026-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147855972","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Affinity-matured B cell responses neutralizing type-I interferons underlie severe viral infections.","authors":"Morgane Fournier, Matthias Vanderkerken, Karim Dorgham, Paul Bastard, Olivia Ahouzi, Stephane Duquerroy, Ngoc Khanh Nguyen, Manon Broutin, Manon Charlet, Alexis Vandenberghe, Paolo Van Endert, Lucy Bizien, Omaira Da Mata-Jardin, Andrés Ferriño-Iriarte, Ahmed Haouz, Thibaut Belmondo, Sophie Hüe, Alessandro Borghesi, Carlos Rodríguez-Gallego, Donald C Vinh, Evangelos Andreakos, Filomeen Haerynck, Rabih Halwani, Qiang Pan-Hammarström, Niklas K Björkström, Benedikt Strunz, Trine H Mogensen, Antonio Piralla, Stefania Varchetta, Jorge Freixinet, Lucie Roussel, Sophie Trouillet Assant, Bénédicte Neven, Romain Levy, Tom le Voyer, Ottavia M Delmonte, Cliona O'Farrelly, Jacques Rivière, Blanca Amador Borrero, Amélie Servettaz, Roger D Kouyos, Daniel E Kaufmann, Etienne Crickx, Marc Michel, Anne Puel, Laurent Abel, Charles-Edouard Luyt, Alexis Mathian, Kai Kisand, Darragh Duffy, Lluis Quintana-Murci, Zahir Amoura, Benjamin G Hale, Jean-Claude Weill, Jean-Laurent Casanova, Felix A Rey, Guy Gorochov, Pascal Chappert, Matthieu Mahévas","doi":"10.1016/j.cell.2026.04.013","DOIUrl":"https://doi.org/10.1016/j.cell.2026.04.013","url":null,"abstract":"<p><p>Autoantibodies neutralizing type-I interferons (AAN-I-IFNs) emerge as global, common, and strong determinants of a growing number of severe viral diseases. We report that AAN-I-IFNs⁺ patients with life-threatening COVID-19 pneumonia harbor circulating type-I IFN-specific B cells indistinguishable from patients bearing T cell tolerance defects of genetic origin. This autoimmune response mobilizes a highly diverse and stable circulating B cell response that is detected prior to severe viral infection and acquires high affinity and neutralization potential to type-I IFNs through extended somatic hypermutation. X-ray crystallography and AlphaFold3 structural analysis of hundreds of patient-derived monoclonal antibodies reveals the extended breadth of this response, targeting three major B cell epitopes covering all facets of type-I IFNs. These findings support a model in which a germinal-center-derived memory B cell response directed against type-I IFNs is established before severe viral infection, providing a core mechanism linking T cell tolerance defect to pathogenic AAN-I-IFNs underlying severe viral diseases.</p>","PeriodicalId":9656,"journal":{"name":"Cell","volume":" ","pages":""},"PeriodicalIF":42.5,"publicationDate":"2026-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147834291","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}