Ketoconazole抑制Th17细胞胆固醇代谢逆转非酒精性脂肪性肝炎的机制研究

胆固醇代谢紊乱与多种重大疾病相关。非酒精性脂肪性肝炎（NASH）以T细胞比例与功能失调为特征，而T细胞功能可受胆固醇代谢产物调控，故T细胞的胆固醇代谢紊乱是NASH的主要诱因之一，但目前尚无有效药物。Ketoconazole可抑制胆固醇代谢关键酶CYP51，是治疗真菌性皮肤病常用药。我们前期发现它可以抑制胆固醇前体desmosterol累积和Th17细胞活化，降低NASH炎症水平，提示其具有抑制Th17细胞胆固醇代谢逆转NASH作用（已申请国家发明专利：202010204924.9）。本项目将通过单细胞测序、代谢流特征谱示踪、聚合物胶束纳米偶联等技术，阐明ketoconazole阻断Th17胆固醇代谢流，进而通过STAT3-RORγt/IL-17A通路抑制Th17细胞功能活化的分子机制，并在临床前研究阐释其NASH逆转治疗作用，为其向临床治疗转化奠定基础，具有重要理论和实际应用价值。

The disorder of cholesterol metabolism is related to many major diseases. Nonalcoholic steatohepatitis (NASH) is characterized by the disproportion and dysfunction of T cells, while the function of T cells can be regulated by cholesterol metabolites. Thus, the disorder of cholesterol metabolism of T cells is one of the main causes of NASH, which however has no effective drug yet. Ketoconazole can inhibit the key enzyme CYP51 in cholesterol metabolism and is a common drug for the treatment of fungal dermatosis. We previously found that it could inhibit the accumulation of cholesterol precursor desmosterol and the activation of Th17 cells, reduced the inflammation level of NASH, indicating that it can block cholesterol metabolism in Th17 cells and reverse NASH (National invention patent application No. 202010204924.9). By the techniques including single cell sequencing, metabolic flux tracing and polymer micelles nanocoupling, the purpose of this project is to elucidate the molecular mechanism of ketoconazole in blocking Th17 cholesterol metabolic flow, and subsequently inhibiting the functional activation of Th17 cells through STAT3-RORγt/IL-17A pathway. This project is also dedicated to reveal the therapeutic effect of ketoconazole for NASH in preclinical studies, laying a foundation for its transformation to clinical treatment, which is of great theoretical and practical application value.