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This study reports markedly increased FK506-binding protein 51 (FKBP5) in sepsis-related ARDS patients, linked to cytokine levels and clinical severity. Using sepsis-induced ARDS models in Fkbp5−/− and bone-marrow chimeric mice, non-hematopoietic FKBP5 reduces inflammatory injury. Single-cell transcriptomics identify fibroblasts and epithelial cells as main sources, and conditional fibroblast FKBP5 deletion confirms its critical role. Mechanistically, FKBP5-driven necroptosis triggers NF-κB activation, cytokine release, neutrophil recruitment, and an inflammatory microenvironment, supporting fibroblast FKBP5 targeting.",{"@graph":69,"@context":122},[70,84,105],{"@type":71,"itemListElement":72},"BreadcrumbList",[73,77,79,82],{"item":74,"name":75,"@type":76,"position":8},"https://docshare.wps.com","Home","ListItem",{"item":78,"name":9,"@type":76,"position":14},"https://docshare.wps.com/document/",{"item":80,"name":35,"@type":76,"position":81},"https://docshare.wps.com/document/healthcare/",3,{"item":83,"name":65,"@type":76,"position":19},"https://docshare.wps.com/document/fkbp5-mediates-alveolar-fibroblast-necroptosis-during-acute-respiratory-distress-syndrome/455472/",{"url":83,"name":65,"@type":85,"image":86,"author":91,"headline":65,"publisher":94,"fileFormat":97,"inLanguage":63,"description":67,"dateModified":98,"datePublished":99,"encodingFormat":97,"isAccessibleForFree":100,"interactionStatistic":101},"DigitalDocument",{"url":87,"@type":88,"width":89,"height":90},"https://docshare.wps.com/thumbnails/fkbp5-mediates-alveolar-fibroblast-necroptosis-during-acute-respiratory-distress-syndrome/455472.png","ImageObject",300,407,{"name":92,"@type":93},"Patrick","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-11-06","2026-09-30",true,{"@type":102,"interactionType":103,"userInteractionCount":44},"InteractionCounter",{"@type":104},"ViewAction",{"@type":106,"mainEntity":107},"FAQPage",[108,114,118],{"name":109,"@type":110,"acceptedAnswer":111},"What role does FKBP5 play in ARDS inflammation?","Question",{"text":112,"@type":113},"FKBP5 expression is increased in sepsis-related ARDS and is associated with higher cytokine levels and disease severity. The study also shows that fibroblast FKBP5 is essential for driving the inflammatory response.","Answer",{"name":115,"@type":110,"acceptedAnswer":116},"How was the effect of non-hematopoietic FKBP5 tested?",{"text":117,"@type":113},"The study used sepsis-induced ARDS models in Fkbp5−/− and bone marrow chimeric mice to demonstrate that non-hematopoietic FKBP5 mitigates inflammatory injury.",{"name":119,"@type":110,"acceptedAnswer":120},"What mechanism links FKBP5 to inflammation in alveolar fibroblasts?",{"text":121,"@type":113},"FKBP5-mediated necroptosis of alveolar fibroblasts activates NF-κB, promotes proinflammatory cytokine release, recruits neutrophils, and sustains an inflammatory microenvironment in alveolar epithelial tissue.","https://schema.org",{"og:url":83,"og:type":124,"og:title":65,"og:site_name":95,"og:description":67},"article",{"robots":126,"canonical":83},"index,follow",{"doc_id":128,"site_id":62},455472,1790812934,{"code":4,"msg":5,"data":131},{"doc_id":128,"user_id":132,"nickname":92,"user_avatar":133,"doc_module":4,"category_id":34,"category_name":35,"doc_title":65,"doc_description":67,"doc_content":134,"file_id":135,"file_url":136,"file_type":137,"file_size":138,"view_count":44,"is_deleted":4,"is_public":8,"is_downloadable":8,"audit_status":8,"page_count":139,"language":140,"language_code":63,"site_id":62,"html_lang":63,"table_of_contents":141,"faqs":142,"seo_title":143,"seo_description":67,"update_tm":144,"read_time":36,"preview_page_count":4},549758146520,"https://ap-avatar.wpscdn.com/avatar/80002397d8c0411e94?_k=1775819394049821470","Cell Proliferation  \nORIGINAL ARTICLE  OPEN ACCESS   \nFKBP5 Mediates Alveolar Fibroblast Necroptosis During Acute Respiratory Distress Syndrome  \nDong Zhang1  | Wei Liu1 | Ting Sun1 | Yangyang Xiao2 | Qiuwen Chen1 | Xiao Huang3 | Xiaozhi Wang1 | Qian Qi4 | Hao Wang5 | Tao Wang1  \n1Department of Intensive Care Unit, Binzhou Medical University Hospital, Binzhou, Shandong, China | 2Department of Clinical Laboratory, Binzhou Medical University Hospital, Binzhou, Shandong, China | 3Department of Medical Technology, Binzhou Polytechnic, Binzhou, Shandong, China | 4Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Shandong First Medical University and Shandong Provincial Qianfoshan Hospital, Shandong Institute of Respiratory Diseases, Jinan, China | 5Department of Critical Care Medicine, Qilu Hospital of Shandong University, Jinan, Shandong, China  \nCorrespondence: Xiaozhi Wang ([hxicuwxz@163.com](hxicuwxz@163.com)) | Qian Qi ([qiqianqlh@163.com](qiqianqlh@163.com)) | Hao Wang ([wanghao34@126.com](wanghao34@126.com)) | Tao Wang (wtsjr@163. com)  \nReceived: 12 February 2025 | Revised: 7 May 2025 | Accepted: 22 May 2025  \nFunding: This work was supported by funding from the Noncommunicable Chronic Diseases-National Science and Technology Major Project (2024ZD0529700, 2024ZD0529704), National Natural Science Foundation of China (81670078), Taishan Scholar Project of Shandong Province, Key Clinical Specialty Project of Shandong Province, Shandong Province Natural Science Foundation (ZR2024MH116, ZR2024MH153), Shandong Postdoctoral Science Foundation, Doctoral Project Foundation of Binzhou Medical University Hospital.  \nKeywords: acute respiratory distress syndrome | alveolar fibroblast | inflammatory storm | necroptosis  \nABSTRACT  \nThe inflammatory storm is a hallmark of acute respiratory distress syndrome (ARDS), yet effective therapies remain unavailable. FK506-binding protein 51 (FKBP5) has emerged as a regulator of inflammatory responses. In this study, FKBP5 expression was markedly increased in patients with sepsis and correlated with both cytokine levels and disease severity. Using sepsis-induced ARDS models in Fkbp5−/− and bone marrow chimeric mice, this study demonstrated that non-haematopoietic FKBP5 mitigates inflammatory injury. Single-cell transcriptomic analysis identified fibroblasts and epithelial cells as the primary sources of non-haematopoietic FKBP5 in the lung injury. Conditional deletion of FKBP5 in fibroblasts (Col1a2-iCre Fkbp5flox/flox) confirmed the essential role of fibroblast FKBP5 in the inflammatory response during ARDS. Mechanistically, FKBP5-mediated necroptosis of alveolar fibroblasts triggered NF-κB activation, proinflammatory cytokine release, neutrophil recruitment, and the establishment of an inflammatory microenvironment in alveolar epithelial tissue. These findings suggest a potential therapeutic strategy targeting fibroblast FKBP5 and provide a foundation for future clinical investigation in ARDS management.  \n1 | Introduction  \nAcute respiratory distress syndrome (ARDS) is a prevalent and severe condition that poses a significant threat to human health. Epidemiological studies indicate that ARDS patients constitute  \napproximately 10% of all individuals hospitalised in intensive care units, with a mortality rate ranging from 30% to 50%[1] . ARDS represents a critical public health challenge that necessitates immediate attention and intervention [2] . The aetiology of ARDS is diverse, with sepsis identified as the primary  \n\n| Dong Zhang and Wei Liu contributed mainly to this study. |\n| --- |\n| This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.\u003Cbr>© 2025 The Author(s). Cell Proliferation published by Beijing Institute for Stem Cell and Regenerative Medicine and John Wiley & Sons Ltd. |\n\nCell Proliferation, 2026; 5","cbCairMSxY2CfVfd","https://ap.wps.com/l/cbCairMSxY2CfVfd","pdf",7452436,16,"English","# Introduction\n## Inflammatory response and cytokine-driven mechanisms\n## Triggers and immune cell recruitment in ARDS\n## Current therapeutic approaches and limitations\n# Mechanistic focus on FKBP5 and fibroblast necroptosis","[{\"question\":\"What role does FKBP5 play in ARDS inflammation?\",\"answer\":\"FKBP5 expression is increased in sepsis-related ARDS and is associated with higher cytokine levels and disease severity. The study also shows that fibroblast FKBP5 is essential for driving the inflammatory response.\"},{\"question\":\"How was the effect of non-hematopoietic FKBP5 tested?\",\"answer\":\"The study used sepsis-induced ARDS models in Fkbp5−/− and bone marrow chimeric mice to demonstrate that non-hematopoietic FKBP5 mitigates inflammatory injury.\"},{\"question\":\"What mechanism links FKBP5 to inflammation in alveolar fibroblasts?\",\"answer\":\"FKBP5-mediated necroptosis of alveolar fibroblasts activates NF-κB, promotes proinflammatory cytokine release, recruits neutrophils, and sustains an inflammatory microenvironment in alveolar epithelial tissue.\"}]","FKBP5 Mediates Alveolar Fibroblast Necroptosis During Acute Respiratory Distress Syndrome | PDF",1790743121]