非酒精性脂肪性肝炎（NASH）所致肝癌的发病率呈上升趋势，临床上尚无有效控制NASH及进展的药物，发现和确证NASH相关肝癌进展中新靶点并研发药物是预防和治疗NASH相关肝癌的重要手段。p62是促进NASH相关肝癌的关键蛋白。前期研究发现DDX5在NASH相关肝癌小鼠模型中下调，DDX5表达量与p62负相关，与肝癌病人预后正相关。DDX5与p62互作促进自噬及p62降解。Hypercalin B（HB）可上调DDX5蛋白，提示其在NASH相关肝癌治疗上有一定的潜力。据此本项目拟在体内外模型中研究DDX5与p62互作调控自噬及炎症抑制NASH相关肝癌进展的分子机理；研究HB上调DDX5蛋白的分子机制，利用DDX5肝脏条件性高表达或敲除小鼠探索其在NASH相关肝癌模型中药效与作用机制；最终阐明DDX5抑制NASH相关肝癌进展的机理，揭示HB调控DDX5在体内外抗NASH相关肝癌的分子机制。

Non-alcoholic steatohepatitis-associated hepatocellular carcinoma (NASH-HCC) is a malignancy whose incidents is rapidly increasing. To date, no evidence-based drug therapy has been approved for NASH management. To identify new target and develop target-based drug are important strategies for preventing NASH to HCC progression. P62 is the key signaling in promoting NASH-HCC progression. Previously, we found DDX5 decreased in mouse models of NASH and NASH-HCC. DDX5 expression inversely correlates with p62, but positively with the good prognosis in NASH-HCC patients. DDX5 interacted with p62 to promote autophagy and p62 degradation. Hypercalin B could increase the DDX5 protein level but not the mRNA level, indicating its potential role in NASH-HCC therapy. Based on these data, this project intends to study the mechanisms of DDX5 and p62 interaction by regulating autophagy and inflammation suppressing NASH-HCC progression; the mechanism of Hypercalin B increasing DDX5 protein level; employing the DDX5 conditional knockin/knockout mice to establish NASH-HCC mouse models, investigating the effect and mechanism of Hypercalin B. Finally, uncover the mechanisms of DDX5 in NASH-HCC progression, shed light on the mechanism of Hypercalin B regulating DDX5 protein in suppressing NASH associated HCC.