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

Area of Science:

• Immunology
• Oncology
• Gastroenterology

Background:

• Chronic inflammation is a significant global driver of cancer development.
• Interleukin 33 (IL-33) initiates cancer-prone chronic inflammation, but its environmental induction mechanisms remain unclear.
• The Toll-like receptor (TLR)3/4-TBK1-IRF3 signaling pathway is implicated in linking environmental factors to inflammation.

Purpose of the Study:

• To elucidate the mechanism by which environmental insults induce IL-33 in chronic inflammation.
• To identify therapeutic agents that can inhibit the IL-33 induction pathway.
• To evaluate the potential of targeting the IRF3-IL-33 axis for cancer prevention.

Main Methods:

• Conducted a drug library screen using FDA-approved compounds to identify IL-33 suppressors.
• Investigated the role of the TLR3/4-TBK1-IRF3 pathway in skin and pancreas inflammation models.
• Utilized pitavastatin to block TBK1 membrane recruitment and activation via mevalonate pathway inhibition.
• Assessed the efficacy of pitavastatin in preventing chronic pancreatitis and associated cancers in preclinical models.
• Analyzed human patient data for IRF3-IL-33 axis activity in chronic pancreatitis and pancreatic cancer, and correlated pitavastatin use with disease risk.

Main Results:

• Demonstrated that TLR3/4-TBK1-IRF3 pathway activation links environmental insults to IL-33 induction.
• Identified pitavastatin as an inhibitor of IL-33 expression by blocking TBK1 recruitment/activation.
• Showed that pitavastatin prevents chronic pancreatitis and subsequent cancers in an IL-33-dependent manner.
• Confirmed high activity of the IRF3-IL-33 axis in human chronic pancreatitis and pancreatic cancer.
• Observed a significant reduction in chronic pancreatitis and pancreatic cancer risk associated with pitavastatin use in patients.

Conclusions:

• Blocking the TBK1-IRF3-IL-33 signaling axis effectively suppresses cancer-prone chronic inflammation.
• Pitavastatin emerges as a potential therapeutic agent for preventing chronic inflammation and its associated cancers.
• Statins, like pitavastatin, offer a safe and promising prophylactic strategy against inflammation-driven cancers.