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The study links environmental insults to IL-33 induction through activation of the Toll-like receptor 3/4–TBK1–IRF3 pathway in skin and pancreas inflammation. Screening an FDA-approved drug library identifies pitavastatin as a potent IL-33 suppressor by blocking TBK1 membrane recruitment/activation via mevalonate pathway inhibition. Pitavastatin prevents chronic pancreatitis and its cancer sequel in an IL-33-dependent manner and shows reduced risk in patient use data.",{"@graph":69,"@context":121},[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/statin-prevents-cancer-development-in-chronic-inflammation-by-blocking-interleukin-33-expression/337792/",{"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/statin-prevents-cancer-development-in-chronic-inflammation-by-blocking-interleukin-33-expression/337792.png","ImageObject",300,407,{"name":92,"@type":93},"Ivy","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-10-27","2026-09-21",true,{"@type":102,"interactionType":103,"userInteractionCount":105},"InteractionCounter",{"@type":104},"ViewAction",11,{"@type":107,"mainEntity":108},"FAQPage",[109,114,117],{"name":110,"@type":111,"acceptedAnswer":112},"Why is interleukin-33 (IL-33) important in chronic inflammation–associated cancer?","Question",{"text":66,"@type":113},"Answer",{"name":115,"@type":111,"acceptedAnswer":116},"How does the Toll-like receptor pathway regulate IL-33 induction?",{"text":66,"@type":113},{"name":118,"@type":111,"acceptedAnswer":119},"What does pitavastatin do to prevent chronic pancreatitis and cancer?",{"text":120,"@type":113},"Pitavastatin suppresses IL-33 expression by blocking TBK1 membrane recruitment/activation through inhibition of the mevalonate pathway. The findings report prevention of chronic pancreatitis and its cancer sequel in an IL-33-dependent manner, with correlating reduced risk in patients.","https://schema.org",{"og:url":83,"og:type":123,"og:title":65,"og:site_name":95,"og:description":67},"article",{"robots":125,"canonical":83},"index,follow",{"doc_id":127,"site_id":62},337792,1790073659,{"code":4,"msg":5,"data":130},{"doc_id":127,"user_id":131,"nickname":92,"user_avatar":132,"doc_module":4,"category_id":34,"category_name":35,"doc_title":65,"doc_description":67,"doc_content":133,"file_id":134,"file_url":135,"file_type":136,"file_size":137,"view_count":105,"is_deleted":4,"is_public":8,"is_downloadable":8,"audit_status":8,"page_count":138,"language":139,"language_code":63,"site_id":62,"html_lang":63,"table_of_contents":140,"faqs":141,"seo_title":142,"seo_description":67,"update_tm":143,"read_time":144},549758252649,"https://ap-avatar.wpscdn.com/avatar/8000253669c5317157?_k=1778319167496531819","Article [https://doi.org/10.1038/s41467-024-48441-8](https://doi.org/10.1038/s41467-024-48441-8)  \nStatin prevents cancer development in chronic inflammation by blocking interleukin 33 expression  \nReceived: 20 April 2023  \n\n| Accepted: 24 April 2024 |\n| --- |\n| |\n| Check for updates |\n\nJong Ho Park1,2,3, Mahsa Mortaja1,2, Heehwa G. Son1,2, Xutu Zhao 1,2,  \nLauren M. Sloat 1,2, Marjan Azin1,2, Jun Wang2, Michael R. Collier4,  \nKrishna S. Tummala5,6,7,8,9, Anna Mandinova2, Nabeel Bardeesy 5,6,7,8, Yevgeniy R. Semenov4,10, Mari Mino-Kenudson 11 & Shadmehr Demehri 1,2,4   \nChronic inflammation is a major cause of cancer worldwide. Interleukin 33 (IL-33) is a critical initiator of cancer-prone chronic inflammation; however, its induction mechanism by environmental causes of chronic inflammation is unknown. Herein, we demonstrate that Toll-like receptor (TLR)3/4-TBK1-IRF3 pathway activation links environmental insults to IL-33 induction in the skin and pancreas inflammation. An FDA-approved drug library screen identifies pitavastatin to effectively suppress IL-33 expression by blocking TBK1 membrane recruitment/activation through the mevalonate pathway inhibition. Accordingly, pitavastatin prevents chronic pancreatitis and its cancer sequelain an IL-33-dependent manner. The IRF3-IL-33 axis is highly active in chronic pancreatitis and its associated pancreatic cancer in humans. Interestingly, pitavastatin use correlates with a significantly reduced risk of chronic pancreatitis and pancreatic cancer in patients. Our findings demonstrate that blocking the TBK1-IRF3-IL-33 signaling axis suppresses cancer-prone chronic inflammation. Statins present a safe and effective prophylactic strategy to prevent chronic inflammation and its cancer sequela.  \nChronic inflammation accounts for 20% of cancers worldwide1–3. Cancer-prone chronic inflammation, such as pancreatitis, inflammatory bowel disease (IBD), and hepatitis, have risen in recent decades, highlighting the urgent need for improved cancer prevention strategies in at-risk populations4–6. For instance, chronic pancreatitis is associated with an eight-fold increase in the risk of pancreatic cancer 5 years after diagnosis7. Several immune cells and factors, including M2  \nmacrophages, mast cells, transforming growth factor (TGF)-β, interleukin 10 (IL-10), and IL-13, have been identified to promote carcinogenesis in chronic inflammation8–12. However, inhibiting these effectors alone or combined to prevent cancer has proven challenging due to their redundant function in cancer promotion13–15. Furthermore, anti-inflammatory medications, including dexamethasone, which can reduce the risk of cancer development by broadly suppressing  \n1Center for Cancer Immunology, Krantz Family Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA. 2Cutaneous Biology Research Center, Department of Dermatology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA. 3Department of Anatomy, School of Medicine, Keimyung University, Daegu, South Korea. 4Department of Dermatology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA. 5Krantz Family Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA. 6Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA, USA. 7Department of Medicine, Harvard Medical School, Boston, MA, USA. 8Cancer Program, Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, USA. 9Quantitative Biosciences, Merck Research Laboratories, Boston, MA, USA. 10Laboratory of Systems Pharmacology, Harvard Program in Therapeutic Science, Harvard Medical School, Boston, USA. 11Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.  \ne-mail: [sdemehri1@mgh.harvard.edu](sdemehri1@mgh.harvard.edu)  \nimmune responses16, have severe side effects, including coagulopathy and immune hyper-ac","cbCaifJdthjok08Q","https://ap.wps.com/l/cbCaifJdthjok08Q","pdf",2783731,15,"English","# Background and rationale\n## IL-33 and the IL-33/ST2 axis in chronic inflammation and cancer\n## Limitations of existing anti-inflammatory strategies\n# Mechanistic pathway\n## Environmental insults and Toll-like receptor 3/4–TBK1–IRF3 signaling\n# Drug discovery and intervention\n## FDA-approved library screening identifies pitavastatin\n## Mevalonate pathway inhibition blocks TBK1 activation\n# Prevention outcomes\n## Pitavastatin blocks pancreatitis and IL-33-dependent cancer sequel\n## Human correlation and translational implications","[{\"question\":\"Why is interleukin-33 (IL-33) important in chronic inflammation–associated cancer?\",\"answer\":\"\"},{\"question\":\"How does the Toll-like receptor pathway regulate IL-33 induction?\",\"answer\":\"\"},{\"question\":\"What does pitavastatin do to prevent chronic pancreatitis and cancer?\",\"answer\":\"Pitavastatin suppresses IL-33 expression by blocking TBK1 membrane recruitment/activation through inhibition of the mevalonate pathway. The findings report prevention of chronic pancreatitis and its cancer sequel in an IL-33-dependent manner, with correlating reduced risk in patients.\"}]","Statin prevents cancer development in chronic inflammation by blocking interleukin 33 expression | PDF",1790020640,38]