内质网应激协同其他许多信号通路在细胞和整个机体水平调控各种生理活动。申请人已发表的研究证实内质网应激蛋白IRE1α在肥胖促进脂肪性肝炎与肝癌的过程中发挥重要作用，但具体分子机制并不清楚。进一步我们采用染色质免疫共沉淀结合二代测序（ChIP-seq）分析发现IRE1α的下游剪接靶点XBP1蛋白大量富集于GDF15的启动子区域，细胞实验也初步证实IRE1α-XBP1信号途径可调控GDF15的基因表达。本项目拟以肝癌细胞系和肝细胞特异性敲除IRE1α的小鼠为研究工具，建立DEN肝癌模型和原位接种肝癌模型，结合临床标本分析，利用细胞生物学和分子生物学等手段探究IRE1α-XBP1途径通过直接调控GDF15表达促进肝癌发生发展的分子机制，揭示GDF15是IRE1α通路调控肝脏肿瘤生长的必需因子，为阐明肝癌的病理学基础提供新的视角。

Endoplasmic reticulum (ER) stress activates the unfolded protein response (UPR) and has been implicated in a variety of cancers, including hepatocellular carcinoma (HCC). We have reported a dual role for inositol-requiring enzyme 1α (IRE1α), the ER-localized UPR signal transducer, in obesity-promoted HCC progression. The downstream molecular(s) or pathway(s) which link IRE1α to HCC development, however, is still unclear. In preliminary study of our current project, we found that growth differentiation factor 15 (GDF15) acts as a novel target gene of XBP1s in HCC cells according to the results of ChIP-seq. Furthermore, the overexpression of IRE1α or XBP1s dramatically give rise to GDF15 expression in HCC cells. To elucidate the role of GDF15 in IRE1α-promoted HCC progression, liver-specific IRE1α knockout mouse will be utilized in different mouse HCC models. Our study aims to illustrate the underlying pathological molecular mechanisms of IRE1α signaling in promoting HCC progression. Results of this study will support that targeting the IRE1α pathway may serve as an intriguing strategy for developing potential HCC therapeutics.