研究表明促进白色脂肪细胞褐色化可以增强动物机体的能量消耗，缓解肥胖及相关代谢性疾病的症状。已知JAK/STAT通路与脂肪细胞的形成及功能密切相关，并且可以调控白色脂肪细胞褐色化。但是，JAK/STAT通路调控白色脂肪细胞褐色化的分子机制尚不清楚；而且利用STAT调节剂促进白色脂肪细胞褐色化也未见报道。本课题组前期实验表明STAT3通路选择性抑制剂ML116能促进白色脂肪细胞褐色化。本项目拟1）设计合成大量ML116的衍生物进行构效关系研究，发现选择性和活性更好的先导化合物；2）鉴定ML116在白色脂肪细胞褐色化过程中的确切靶点，揭示STAT3通路促进白色脂肪细胞褐色化的分子机制；3）在以上研究基础之上全方位优化先导化合物，为临床研究提供优质的候选分子。本研究将加深我们对STAT3通路调控脂肪细胞命运的理解，为肥胖及相关代谢性疾病提供新型药物靶标和安全有效的药物分子。

Studies have shown promoting the browning of white adipocytes can enhance the body's energy consumption and alleviate the symptoms of obesity and related metabolic diseases. The JAK/STAT pathway is closely related to the formation and functions of adipocytes and can regulate the browning of white adipocytes. However, the molecular mechanism by which the JAK/STAT pathway regulates the browning of white adipocytes is unclear; besides, promoting the browning of white adipocytes by STAT modulators has not been reported. Our preliminary experiments showed that ML116, a selective STAT3 pathway inhibitor, can promote the browning of white fat cells. In the current study, we will first design and synthesize a number of ML116 derivatives to identify the structure-activity relationship and discover a few lead compounds with better selectivity and activity. Secondly, we will identify the targets of ML116 in the browning process, revealing the molecular mechanism by which the STAT3 pathway promotes the browning of white adipocyte. Thirdly, we will further optimize the lead compounds on the basis of the above data to provide high-quality candidates for clinical research. This study will deepen our understanding of how STAT3 pathway regulates the cell fate of adipocytes, and provide novel therapeutic targets and effective candidates for treating obesity and related metabolic diseases.