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斯坦丁可以通过阻断介质蛋白33的表达来预防慢性炎症的癌症发展

Jong Ho Park^1,2,3, Mahsa Mortaja^1,2, Heehwa G Son^1,2

¹Center for Cancer Immunology, Krantz Family Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.

Nature communications

|May 30, 2024

概括

环境侮辱通过托尔类受体 (TLR) 3/4-TBK1-IRF3通路触发慢性炎症和癌症,导致交叉蛋白33 (IL-33) 诱导. 皮塔瓦斯塔丁抑制了这个轴,防止炎症和相关的癌症.

科学领域:

免疫学免疫学免疫学
在瘤学瘤学.
胃肠病学胃肠病学

背景情况:

慢性炎症是全球癌症发展的重要驱动因素.
介质蛋白33 (IL-33) 启动易患癌症的慢性炎症,但其环境诱导机制尚不清楚.
托尔类受体 (TLR) 3/4-TBK1-IRF3信号通路涉及将环境因素与炎症联系起来.

研究的目的:

阐明环境侮辱在慢性炎症中诱导IL-33的机制.
为了确定可以抑制IL-33诱导途径的治疗剂.
评估针对IRF3-IL-33轴的向癌症预防的潜力.

主要方法:

使用FDA批准的化合物进行药物图书馆选,以确定IL-33抑制剂.
研究了TLR3/4-TBK1-IRF3通路在皮肤和胰腺炎症模型中的作用.
利用皮塔瓦斯塔丁阻断TBK1膜招募和激活,通过抑制美瓦酸路径.
在临床前模型中评估了皮塔瓦斯塔丁在预防慢性胰腺炎和相关癌症方面的疗效.
分析了针对慢性胰腺炎和胰腺癌中IRF3-IL-33轴活性的人类患者数据,以及与疾病风险相关的皮塔瓦斯塔丁使用情况.

主要成果:

证明TLR3/4-TBK1-IRF3通路激活将环境侮辱与IL-33诱导联系起来.
通过阻断TBK1的招募/激活,确定皮塔瓦斯塔丁是IL-33表达的抑制剂.
表明皮塔瓦斯塔丁可以以依赖IL-33的方式预防慢性胰腺炎和随后的癌症.
在人类慢性胰腺炎和胰腺癌中确认IRF3-IL-33轴的高活性.
观察到慢性胰腺炎和胰腺癌风险的显著降低与患者使用皮塔瓦斯塔丁相关.

结论:

阻断TBK1-IRF3-IL-33信号轴有效抑制易患癌症的慢性炎症.
皮塔瓦斯塔丁成为预防慢性炎症及其相关癌症的潜在治疗剂.
像皮塔瓦斯塔丁一样,他类药物提供了一种安全而有前途的预防策略,可以预防由炎症驱动的癌症.

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