代谢性脂肪肝病NAFLD发病机理复杂多因，高脂摄入与超负荷代谢是肝脂质代谢紊乱的首要原因，线粒体损伤首当其冲，但病理分子机制不明严重阻碍针对线粒体功能修复和NAFLD的药物研发进展。死亡相关凋亡诱导蛋白激酶Drak2，是细胞凋亡的正性调节因子。前期研究中发现多种非酒精性脂肪肝动物模型肝脏中Drak2蛋白表达及活性显著升高与肝脂肪变性呈正相关；采用AAV病毒干扰和条件性敲除肝脏中Drak2的小鼠均表现出对高脂诱导肝脂肪变性的抵抗、炎症浸润缓解以及线粒体功能增强。通过蛋白磷酸组学质谱、转录组学及蛋白间相互作用组学分析我们发现Drak2可能通过核内RNA选择性剪接体，尤其是SRSF6蛋白，影响线粒体蛋白基因的选择性剪接介导非酒精性脂肪肝的病理过程。本项目以Drak2为切入点，聚焦RNA选择性剪接与线粒体功能，探讨Drak2介导线粒体功能与肝脂肪变性的分子机制，以期为NAFLD治疗提供原创靶标。

Nonalcoholic fatty liver disease (NAFLD) is a worldwide metabolic disorder, which has become a severe public health problem and requires emergent demand of clinical intervention. Death and apoptosis-associated protein kinase 2 (Drak2) is a member of the death-associated protein kinase (DAPK) family, which plays important roles in T cells survival and differentiation, islets survival and cell apoptosis. Drak2-/- mice are resistance to experimental autoimmune encephalitis and type 1 diabetes..Herein, we revealed that Drak2 is significantly upregulated in fatty livers, and its AAV-shRNA interference specifically in liver ameliorates high-fat diet (HFD) induced liver steatosis. Furthermore we demonstrated that Drak2 liver-deficient mice protect against high-fat diet (HFD)-induced liver steatosis, and with improved hepatic mitochondrial function. Comprehensive proteome, phosphoproteome and interactome analysis for Drak2 network, reveals new roles of Drak2, especially enriched in RNA alternative splicing. Among the potential substrates identified, we show that serine/arginine-rich splicing factor 6 (SRSF6), a key factor involved in constitutive splicing and the selection of alternative splice sites, maybe a substrate of Drak2. The transcriptome analysis of primary hepatocytes from Drak2-dificiency and control mice reveals that Drak2 mediated liver steatosis maybe through SRSF6 associated RNA alternative splicing of target mitochondrial function genes. .In conclusions, our findings reveal for the first time an indispensable role of Drak2 in hepatic steatosis through regulating SRSF6 associated RNA alternative splicing, may offer a potential therapeutic target for NAFLD.