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

Sep 21, 2026

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Statin therapy prevents cancer development driven by chronic inflammation by suppressing interleukin-33 (IL-33) expression. 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.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages15

Reading Time38 min

AccessFree to download

Background and rationale

IL-33 and the IL-33/ST2 axis in chronic inflammation and cancer

Limitations of existing anti-inflammatory strategies

Mechanistic pathway

Environmental insults and Toll-like receptor 3/4–TBK1–IRF3 signaling

Drug discovery and intervention

FDA-approved library screening identifies pitavastatin

Mevalonate pathway inhibition blocks TBK1 activation

Prevention outcomes

Pitavastatin blocks pancreatitis and IL-33-dependent cancer sequel

Human correlation and translational implications

Article [https://doi.org/10.1038/s41467-024-48441-8](https://doi.org/10.1038/s41467-024-48441-8) Statin prevents cancer development in chronic inﬂammation by blocking interleukin 33 expression Received: 20 April 2023 | Accepted: 24 April 2024 | | --- | | | | Check for updates | Jong Ho Park1,2,3, Mahsa Mortaja1,2, Heehwa G. Son1,2, Xutu Zhao 1,2, Lauren M. Sloat 1,2, Marjan Azin1,2, Jun Wang2, Michael R. Collier4, Krishna 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 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 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. Chronic 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 macrophages, 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 1Center 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. e-mail: [sdemehri1@mgh.harvard.edu](sdemehri1@mgh.harvard.edu) immune responses16, have severe side effects, including coagulopathy and immune hyper-ac

FAQs

What does pitavastatin do to prevent chronic pancreatitis and cancer?

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.

Sep 21, 2026

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