[{"data":1,"prerenderedAt":-1},["ShallowReactive",2],{"detail-sidebar-cat-0-en-105":3,"doc-detail-446802-en":59,"doc-seo-446802-105":80},{"code":4,"msg":5,"data":6},0,"success",[7,13,18,23,28,33,38,43,48,51,55],{"id":8,"doc_module":4,"doc_module_name":9,"category_name":10,"show_sort_weight":11,"slug":12},1,"Document","Story & Novel",90,"story-novel",{"id":14,"doc_module":4,"doc_module_name":9,"category_name":15,"show_sort_weight":16,"slug":17},2,"Literature",80,"literature",{"id":19,"doc_module":4,"doc_module_name":9,"category_name":20,"show_sort_weight":21,"slug":22},4,"Exam",70,"exam",{"id":24,"doc_module":4,"doc_module_name":9,"category_name":25,"show_sort_weight":26,"slug":27},5,"Comic",60,"comic",{"id":29,"doc_module":4,"doc_module_name":9,"category_name":30,"show_sort_weight":31,"slug":32},6,"Technology",50,"technology",{"id":34,"doc_module":4,"doc_module_name":9,"category_name":35,"show_sort_weight":36,"slug":37},7,"Healthcare",40,"healthcare",{"id":39,"doc_module":4,"doc_module_name":9,"category_name":40,"show_sort_weight":41,"slug":42},8,"Research & Report",30,"research-report",{"id":44,"doc_module":4,"doc_module_name":9,"category_name":45,"show_sort_weight":46,"slug":47},9,"Religion & Spirituality",20,"religion-spirituality",{"id":46,"doc_module":4,"doc_module_name":9,"category_name":49,"show_sort_weight":46,"slug":50},"World Cup","world-cup",{"id":52,"doc_module":4,"doc_module_name":9,"category_name":53,"show_sort_weight":52,"slug":54},10,"Lifestyle","lifestyle",{"id":56,"doc_module":4,"doc_module_name":9,"category_name":57,"show_sort_weight":24,"slug":58},19,"General","general",{"code":4,"msg":5,"data":60},{"doc_id":61,"user_id":62,"nickname":63,"user_avatar":64,"doc_module":4,"category_id":39,"category_name":40,"doc_title":65,"doc_description":66,"doc_content":67,"file_id":68,"file_url":69,"file_type":70,"file_size":71,"view_count":14,"is_deleted":4,"is_public":8,"is_downloadable":8,"audit_status":8,"page_count":56,"language":72,"language_code":73,"site_id":74,"html_lang":73,"table_of_contents":75,"faqs":76,"seo_title":77,"seo_description":66,"update_tm":78,"read_time":79},446802,2336478951081,"Ben ","https://ap-avatar.wpscdn.com/davatar_276721f389ce27ea32af1340a28f341c","Cathepsin S Contributes to Influenza-Induced Lung Injury by Driving Inflammation, Promoting Apoptosis, and Disrupting Epithelial Barrier Integrity","Influenza virus infection causes substantial morbidity and mortality worldwide, and severe disease is frequently driven by excessive host inflammation together with compromised epithelial barrier function. This study identifies cathepsin S (CTSS), a lysosomal cysteine protease, as a central mediator of influenza-induced lung injury. Infection upregulates CTSS in a time- and dose-dependent manner, triggering lysosomal membrane permeabilization, CTSS release, enhanced apoptosis, and loss of epithelial barrier integrity. CTSS knockdown reduces cytokine production, apoptosis, and barrier disruption in vitro, while CTSS inhibition in infected mice alleviates inflammation and severity without altering viral titers. TNF-α activates CTSS but does not restore apoptosis or inflammatory responses in CTSS-silenced cells, indicating a downstream role of CTSS in cytokine signaling. Overall, CTSS links viral infection and cytokine storm to epithelial damage and emerges as a promising host-directed therapeutic target.","| Host-Microbial Interactions | Research Article  \nCathepsin S contributes to influenza-induced lung injury by driving inflammation, promoting apoptosis, and disrupting epithelial barrier integrity  \nTianxin Ma,1 Chunguang Yang,1,2 Yang Wang,1,2,3,4 Chuanmeizi Tu,1 Jiawei Zhang,1 Kailin Mai,1 Shengzhen Wu,1 Hongxuan Zhou,5 Shengfeng Li,5 Sulan Ye,1 Lixi Liang,1 Qingsheng Huang,1 Zhenhui Zhang,5 Zhengshi Lin,1 Weiqi Pan,1,3,4 Zifeng Yang1,2,3,4  \nAUTHOR AFFILIATIONS See affiliation list on p. 16.  \nABSTRACT Influenza virus infection causes significant morbidity and mortality worldwide, with severe cases often driven by excessive host inflammatory responsesand disruption of epithelial barrier function. Here, we identified cathepsin S (CTSS), a lysosomal cysteine protease, as a key mediator of influenza-induced lung injury. Influenza virus infection upregulated CTSS in a time-dependent and dose-dependent manner, leading to lysosomal membrane permeabilization and cytoplasmic release of CTSS, which correlated with increased apoptosis and loss of epithelial barrier integrity. Knockdown of CTSS reduced proinflammatory cytokine production, apoptosis, and barrier disruption in A549 cells. Air–liquid interface airway epithelial cultures further validated the essential role of CTSS in preserving epithelial barrier integrity. In vivo, pharmacological inhibition of CTSS alleviated lung inflammation and disease severity in infected mice without reducing viral titers. Tumor necrosis factor-alpha (TNF-α) strongly induced CTSS activation, but failed to restore apoptosis and inflammatory responsesin CTSS-knockdown cells, suggesting that CTSS acts downstream of cytokine signaling. These findings reveal a central role for CTSS in linking viral infection, cytokine storm, and epithelial damage and highlight CTSS as a promising target for host-directed therapy against severe influenza.  \nIMPORTANCE Severe influenza is often driven by excessive host inflammation and epithelial barrier disruption, yet the molecular mediators connecting viral infection to these pathological processes remain poorly defined. This study identifies cathepsin S (CTSS) as a central driver of influenza-induced epithelial injury, acting downstream of viral replication and cytokine signaling to promote apoptosis, inflammation, and barrier disruption. Using both in vitro and in vivo models, we demonstrate that inhibiting CTSS preserves barrier integrity and attenuates inflammation despite having no beneficial effect on viral clearance. These findings provide mechanistic insight into influenza pathogenesis and support CTSS as a promising target for host-directed interventions to mitigate cytokine storm-driven lung injury in severe respiratory viral infections.  \nKEYWORDS cathepsin S, inflammatory response, apoptosis, epithelial barrier I nfluenza is an acute, highly contagious respiratory disease caused by influenza viruses  \nthat occur annually and occasionally cause pandemics (1) . Globally, influenza is estimated to cause approximately 1 billion infections each year, including 3–5 million cases of severe illness and 290,000–650,000 respiratory-related deaths (2, 3) . Typical clinical features include the sudden onset of fever, cough, sore throat, myalgia, and fatigue (4, 5) . While most cases are self-limiting, the disease can rapidly progress to severe complications in vulnerable populations, including acute lung injury and, in  \nEditor Leiliang Zhang, Shandong First Medical University, Jinan, Shandong, China  \nAddress correspondence to Zifeng Yang, [jeffyah@163.com](jeffyah@163.com), Weiqi Pan, [panweiqi@gird.cn](panweiqi@gird.cn), Zhengshi Lin, [zslingz@163.com](zslingz@163.com), or Zhenhui Zhang, [zzhmed@126.com](zzhmed@126.com).  \nTianxin Ma, Chunguang Yang, Yang Wang, and Chuanmeizi Tu contributed equally to this article.  \nThe authors are listed in an order mutually agreed by all authors  \ncritical cases, acute respiratory distress syndrome with multi-organ dysfunction,","cbCaiiqhPGBZQMTa","https://ap.wps.com/l/cbCaiiqhPGBZQMTa","pdf",2741470,"English","en",105,"# Abstract\n# Importance\n# Background and Rationale\n## Role of epithelial barrier disruption in severe influenza\n## Cathepsin S structure and biological functions\n## Gap in current mechanistic understanding\n# Study focus and main findings","[{\"question\":\"What role does cathepsin S (CTSS) play in influenza-induced lung injury?\",\"answer\":\"CTSS is identified as a key mediator that links influenza infection to excessive inflammation, apoptosis, and epithelial barrier damage.\"},{\"question\":\"How does influenza infection affect CTSS during disease progression?\",\"answer\":\"Influenza infection upregulates CTSS in a time-dependent and dose-dependent manner, which is associated with lysosomal membrane permeabilization and CTSS release.\"},{\"question\":\"Does inhibiting CTSS reduce viral load in infected animals?\",\"answer\":\"No. Pharmacological inhibition of CTSS alleviates lung inflammation and disease severity in mice without reducing viral titers.\"}]","Cathepsin S Contributes to Influenza-Induced Lung Injury by Driving Inflammation, Promoting Apoptosis, and Disrupting Epithelial Barrier Integrity | PDF",1790717263,48,{"code":4,"msg":81,"data":82},"ok",{"site_id":74,"language":73,"slug":83,"title":65,"keywords":84,"description":66,"schema_data":85,"social_meta":139,"head_meta":141,"extra_data":143,"updated_unix":144},"cathepsin-s-contributes-to-influenza-induced-lung-injury-by-driving-inflammation-promoting-apoptosis-and-disrupting-epithelial-barrier-integrity","",{"@graph":86,"@context":138},[87,101,121],{"@type":88,"itemListElement":89},"BreadcrumbList",[90,94,96,99],{"item":91,"name":92,"@type":93,"position":8},"https://docshare.wps.com","Home","ListItem",{"item":95,"name":9,"@type":93,"position":14},"https://docshare.wps.com/document/",{"item":97,"name":40,"@type":93,"position":98},"https://docshare.wps.com/document/research-report/",3,{"item":100,"name":65,"@type":93,"position":19},"https://docshare.wps.com/document/cathepsin-s-contributes-to-influenza-induced-lung-injury-by-driving-inflammation-promoting-apoptosis-and-disrupting-epithelial-barrier-integrity/446802/",{"url":100,"name":65,"@type":102,"image":103,"author":108,"headline":65,"publisher":110,"fileFormat":113,"inLanguage":73,"description":66,"dateModified":114,"datePublished":115,"encodingFormat":113,"isAccessibleForFree":116,"interactionStatistic":117},"DigitalDocument",{"url":104,"@type":105,"width":106,"height":107},"https://docshare.wps.com/thumbnails/cathepsin-s-contributes-to-influenza-induced-lung-injury-by-driving-inflammation-promoting-apoptosis-and-disrupting-epithelial-barrier-integrity/446802.png","ImageObject",300,407,{"name":63,"@type":109},"Person",{"url":91,"name":111,"@type":112},"DocShare","Organization","application/pdf","2026-09-30","2026-09-29",true,{"@type":118,"interactionType":119,"userInteractionCount":14},"InteractionCounter",{"@type":120},"ViewAction",{"@type":122,"mainEntity":123},"FAQPage",[124,130,134],{"name":125,"@type":126,"acceptedAnswer":127},"What role does cathepsin S (CTSS) play in influenza-induced lung injury?","Question",{"text":128,"@type":129},"CTSS is identified as a key mediator that links influenza infection to excessive inflammation, apoptosis, and epithelial barrier damage.","Answer",{"name":131,"@type":126,"acceptedAnswer":132},"How does influenza infection affect CTSS during disease progression?",{"text":133,"@type":129},"Influenza infection upregulates CTSS in a time-dependent and dose-dependent manner, which is associated with lysosomal membrane permeabilization and CTSS release.",{"name":135,"@type":126,"acceptedAnswer":136},"Does inhibiting CTSS reduce viral load in infected animals?",{"text":137,"@type":129},"No. Pharmacological inhibition of CTSS alleviates lung inflammation and disease severity in mice without reducing viral titers.","https://schema.org",{"og:url":100,"og:type":140,"og:title":65,"og:site_name":111,"og:description":66},"article",{"robots":142,"canonical":100},"index,follow",{"doc_id":61,"site_id":74},1790795370]