The Hippo pathway plays a vital role in tissue homeostasis and tumorigenesis. The transcription factor IRF3 is essential for innate antiviral immunity. In this study, we discovered IRF3 as an agonist of Yes-associated protein (YAP). The expression of IRF3 is positively correlated with that of YAP and its target genes in gastric cancer; the expression of both IRF3 and YAP is up-regulated and prognosticates patient survival. IRF3 interacts with both YAP and TEAD4 in the nucleus to enhance their interaction, promoting nuclear translocation and activation of YAP. IRF3 and YAP–TEAD4 are associated genome-wide to cobind and coregulate many target genes of the Hippo pathway. Overexpression of active IRF3 increased, but depletion of IRF3 reduced, the occupancy of YAP on the target genes. Knockdown or pharmacological targeting of IRF3 by Amlexanox, a drug used clinically for antiinflammatory treatment, inhibits gastric tumor growth in a YAP-dependent manner. Collectively, our study identifies IRF3 as a positive regulator for YAP, highlighting a new therapeutic target against YAP-driven cancers.

河马途径在组织稳态和肿瘤发生中起着至关重要的作用。转录因子IRF3对于先天抗病毒免疫至关重要。在这项研究中，我们发现IRF3是Yes相关蛋白（YAP）的激动剂。胃癌组织中IRF3的表达与YAP及其靶基因的表达呈正相关。IRF3和YAP的表达均被上调并预后了患者的生存。IRF3与原子核中的YAP和TEAD4相互作用，以增强它们的相互作用，促进核易位和激活YAP。IRF3和YAP–TEAD4在全基因组范围内相关联，以共同结合和共聚河马途径的许多靶基因。活性IRF3的过表达增加了，但IRF3的消耗减少了，YAP在靶基因上的占有率。Amlexanox对IRF3的击倒或药理靶向 临床上用于抗炎治疗的药物以YAP依赖性方式抑制胃肿瘤的生长。总体而言，我们的研究确定IRF3为YAP的正调节剂，强调了针对YAP驱动的癌症的新治疗靶标。