[{"data":1,"prerenderedAt":-1},["ShallowReactive",2],{"detail-sidebar-cat-0-en-105":3,"doc-seo-458180-105":59,"doc-detail-458180-en":131},{"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":60,"data":61},"ok",{"site_id":62,"language":63,"slug":64,"title":65,"keywords":66,"description":67,"schema_data":68,"social_meta":124,"head_meta":126,"extra_data":128,"updated_unix":130},105,"en","irhom2-regulates-hmgb1-secretion-to-modulate-inflammation-and-hepatocyte-senescence-in-an-in-vitro-model-of-ischemia-reperfusion-injury","iRhom2 regulates HMGB1 secretion to modulate inflammation and hepatocyte senescence in an in vitro model of ischemia-reperfusion injury","","Ischemia-reperfusion injury in liver transplantation triggers a strong inflammatory program that damages hepatocytes, drives senescence, and impairs long-term graft function. Mechanisms remain incomplete, despite evidence that macrophage-derived signals shape hepatocyte fate. The study identifies iRhom2 as a central regulator of macrophage-driven inflammation and hepatocyte senescence, with iRhom2 upregulated in reperfused allografts. iRhom2 loss in macrophages reduces ER stress, preserves mitochondrial function, attenuates apoptosis, and limits HMGB1-mediated senescence, suggesting therapeutic targeting of the iRhom2-HMGB1 axis.",{"@graph":69,"@context":123},[70,84,106],{"@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/irhom2-regulates-hmgb1-secretion-to-modulate-inflammation-and-hepatocyte-senescence-in-an-in-vitro-model-of-ischemia-reperfusion-injury/458180/",{"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/irhom2-regulates-hmgb1-secretion-to-modulate-inflammation-and-hepatocyte-senescence-in-an-in-vitro-model-of-ischemia-reperfusion-injury/458180.png","ImageObject",300,407,{"name":92,"@type":93},"Aurelia","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-11-02","2026-09-30",true,{"@type":102,"interactionType":103,"userInteractionCount":105},"InteractionCounter",{"@type":104},"ViewAction",13,{"@type":107,"mainEntity":108},"FAQPage",[109,115,119],{"name":110,"@type":111,"acceptedAnswer":112},"What problem does the study address in liver transplantation?","Question",{"text":113,"@type":114},"It addresses ischemia-reperfusion injury, which causes acute dysfunction and contributes to long-term allograft rejection through inflammation, hepatocyte damage, and senescence.","Answer",{"name":116,"@type":111,"acceptedAnswer":117},"How does iRhom2 influence macrophage-driven effects in this work?",{"text":118,"@type":114},"The study shows iRhom2 regulates secretion-related signaling from macrophages and promotes HMGB1 release, leading to hepatocyte senescence under in vitro IRI conditions.",{"name":120,"@type":111,"acceptedAnswer":121},"What is the role of HMGB1 in hepatocyte senescence according to the findings?",{"text":122,"@type":114},"HMGB1 release induces senescence in human iPSC-derived hepatocytes, upregulates senescence markers, disrupts cell-cycle dynamics, and worsens viability; neutralization or knockdown mitigates these effects.","https://schema.org",{"og:url":83,"og:type":125,"og:title":65,"og:site_name":95,"og:description":67},"article",{"robots":127,"canonical":83},"index,follow",{"doc_id":129,"site_id":62},458180,1790789985,{"code":4,"msg":5,"data":132},{"doc_id":129,"user_id":133,"nickname":92,"user_avatar":134,"doc_module":4,"category_id":34,"category_name":35,"doc_title":65,"doc_description":67,"doc_content":135,"file_id":136,"file_url":137,"file_type":138,"file_size":139,"view_count":105,"is_deleted":4,"is_public":8,"is_downloadable":8,"audit_status":8,"page_count":140,"language":141,"language_code":63,"site_id":62,"html_lang":63,"table_of_contents":142,"faqs":143,"seo_title":144,"seo_description":67,"update_tm":145,"read_time":146,"preview_page_count":4},1099514068365,"https://ap-avatar.wpscdn.com/avatar/10000253d8d9f28188e?x-image-process=image/resize,m_fixed,w_180,h_180&k=1794309523707217728","[www.nature.com/cddis](www.nature.com/cddis)  \nARTICLE OPEN   \niRhom2 regulates HMGB1 secretion to modulate inflammation and hepatocyte senescence in an in vitro model of ischemiareperfusion injury  \nMatteo Calligaris1,5, Riccardo Perriera2,5, Claudia Carcione3, Vitale Miceli2, Margot Lo Pinto2, Rosalia Busà2, Giandomenico Amico3, Matteo Bulati2, Caterina Amato2, Duilio Pagano2,4, Pier Giulio Conaldi2, Simone Dario Scilabra3, Massimo Pinzani2 and Giovanni Zito 2 ✉  \n© The Author(s) 2025  \n\n|  | Ischemia-reperfusion injury (IRI) represents a major challenge in liver transplantation, driving acute dysfunction and contributing to long-term allograft rejection. This process triggers a robust inflammatory response, leading to hepatocyte damage, senescence, and impaired liver regeneration. While the underlying mechanisms remain incompletely understood, increasing evidence highlights macrophage-derived signaling as a pivotal driver of hepatocyte fate during IRI. Here, we identify iRhom2 as a key regulator of immune-mediated liver injury, orchestrating macrophage-driven inflammation and hepatocyte senescence. iRhom2 is known to modulate the secretion of multiple cytokines by macrophages, yet its specific contribution to IRI-driven hepatocyte senescence has not been fully elucidated. We reveal a significant upregulation of iRhom2 in IRI+ reperfused allografts, particularly in Kupffer cells and monocyte-derived macrophages. Functional characterization in iRhom2-deficient macrophages revealed reduced ER stress, preserved mitochondrial function, and attenuated apoptosis, indicating a protective role against IRI-induced cellular damage. Proteomic profiling further uncovers iRhom2-dependent secretion of inflammatory mediators, with HMGB1 emerging as a critical damage-associated molecular pattern (DAMP) molecule in this context. Notably, HMGB1 release occurs independently of TACE catalytic activity, suggesting an alternative unexplored regulatory mechanism. Furthermore, co-culture experiments confirm that macrophage-derived HMGB1 directly induces senescence of human induced pluripotent stem cell-derived hepatocytes (hiPSCHeps) under in vitro IRI condition, driving the up-regulation of key senescence markers and disrupting cell cycle dynamics. Strikingly, HMGB1 neutralization enhances hepatocyte viability and mitigates senescence, underscoring its pathogenic role. Additionally, HMGB1 knockdown in macrophages protects hepatocytes, though p21 expression remains unaffected, hinting at additional senescence pathways. Our findings establish iRhom2 as a central orchestrator of macrophage-driven hepatocyte dysfunction in IRI and suggest that targeting the iRhom2-HMGB1 axis could represent a promising therapeutic strategy to improve |  |\n| --- | --- | --- |\n|  |  |  |\n|  |  |  |\n|  |  |  |\n|  |  |  |\n|  |  |  |\n|  |  |  |\n|  |  |  |\n|  |  |  |\n|  |  |  |\n|  |  |  |\n|  |  |  |\n|  |  |  |\n|  |  |  |\n|  |  |  |\n|  |  |  |\n|  |  |  |\n|  |  |  |\n|  |  |  |\n| post-transplant liver recovery and long-term graft survival. |  |  |\n|  | Cell Death and Disease (2026)17:7; [https://doi.org/10.1038/s41419-025-08256-x](https://doi.org/10.1038/s41419-025-08256-x) |  |\n|  |  |  |\n\nINTRODUCTION  \nLiver transplantation is the primary and often the only effective treatment for end-stage liver disease, a condition that is becoming an increasingly significant cause of mortality worldwide. As transplantation rates rise, so does the urgency of addressing associated risks, particularly acute and chronic rejection, which compromise graft survival and patient outcomes [1] . Among the major contributors to graft dysfunction, ischemia-reperfusion injury (IRI) stands out as a critical factor [2, 3] . IRI occurs during the transplantation process, involving two distinct phases: ischemia, when the organ is deprived of oxygen during retrieval, and reperfusion, where oxygen restoration paradoxically exacerbates cellular damage [4, 5] . This multifaceted process initiates a cascade of events, in","cbCaiaFBI6p8lpHs","https://ap.wps.com/l/cbCaiaFBI6p8lpHs","pdf",5465402,11,"English","# Introduction\n## Ischemia-reperfusion injury in liver transplantation\n## Role of iRhom2 and macrophage signaling\n## Study objectives and approach","[{\"question\":\"What problem does the study address in liver transplantation?\",\"answer\":\"It addresses ischemia-reperfusion injury, which causes acute dysfunction and contributes to long-term allograft rejection through inflammation, hepatocyte damage, and senescence.\"},{\"question\":\"How does iRhom2 influence macrophage-driven effects in this work?\",\"answer\":\"The study shows iRhom2 regulates secretion-related signaling from macrophages and promotes HMGB1 release, leading to hepatocyte senescence under in vitro IRI conditions.\"},{\"question\":\"What is the role of HMGB1 in hepatocyte senescence according to the findings?\",\"answer\":\"HMGB1 release induces senescence in human iPSC-derived hepatocytes, upregulates senescence markers, disrupts cell-cycle dynamics, and worsens viability; neutralization or knockdown mitigates these effects.\"}]","iRhom2 regulates HMGB1 secretion to modulate inflammation and hepatocyte senescence in an in vitro model of ischemia-reperfusion injury | PDF",1790751968,28]