Center for Cancer Immunology, Krantz Family Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
Cutaneous Biology Research Center, Department of Dermatology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
Nat Commun. 2024 May 30;15(1):4099. doi: 10.1038/s41467-024-48441-8.
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.
慢性炎症是全球癌症的主要成因。白细胞介素 33（IL-33）是癌症易发性慢性炎症的关键启动子；然而，其诱导机制仍不清楚。在此，我们证明 Toll 样受体（TLR）3/4-TBK1-IRF3 途径的激活将环境刺激与皮肤和胰腺炎症中的 IL-33 诱导联系起来。美国食品和药物管理局批准的药物库筛选发现，匹伐他汀通过抑制甲羟戊酸途径抑制来有效抑制 TBK1 膜募集/激活，从而有效抑制 IL-33 的表达。因此，匹伐他汀以依赖于 IL-33 的方式预防慢性胰腺炎及其癌症后遗症。IRF3-IL-33 轴在人类慢性胰腺炎及其相关胰腺癌中高度活跃。有趣的是，匹伐他汀的使用与慢性胰腺炎和胰腺癌患者的风险显著降低相关。我们的研究结果表明，阻断 TBK1-IRF3-IL-33 信号通路可抑制癌症易发性慢性炎症。他汀类药物是一种安全有效的预防策略，可以预防慢性炎症及其癌症后遗症。
