Statin prevents cancer development in chronic inflammation by blocking interleukin 33 expression

Jong Ho Park, Mahsa Mortaja, Heehwa G. Son, Xutu Zhao, Lauren M. Sloat, Marjan Azin, Jun Wang, Michael R. Collier, Krishna S. Tummala, Anna Mandinova, Nabeel Bardeesy, Yevgeniy R. Semenov, Mari Mino-Kenudson and Shadmehr Demehri ()
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Jong Ho Park: Massachusetts General Hospital and Harvard Medical School
Mahsa Mortaja: Massachusetts General Hospital and Harvard Medical School
Heehwa G. Son: Massachusetts General Hospital and Harvard Medical School
Xutu Zhao: Massachusetts General Hospital and Harvard Medical School
Lauren M. Sloat: Massachusetts General Hospital and Harvard Medical School
Marjan Azin: Massachusetts General Hospital and Harvard Medical School
Jun Wang: Massachusetts General Hospital and Harvard Medical School
Michael R. Collier: Massachusetts General Hospital and Harvard Medical School
Krishna S. Tummala: Massachusetts General Hospital and Harvard Medical School
Anna Mandinova: Massachusetts General Hospital and Harvard Medical School
Nabeel Bardeesy: Massachusetts General Hospital and Harvard Medical School
Yevgeniy R. Semenov: Massachusetts General Hospital and Harvard Medical School
Mari Mino-Kenudson: Massachusetts General Hospital and Harvard Medical School
Shadmehr Demehri: Massachusetts General Hospital and Harvard Medical School

Nature Communications, 2024, vol. 15, issue 1, 1-15

Abstract: Abstract Chronic 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 sequela in 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.

Date: 2024
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DOI: 10.1038/s41467-024-48441-8

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