狼疮性肾炎是我国最常见的继发性免疫性肾小球疾病，是终末期肾脏病的常见病因之一。目前对于临床表现为大量蛋白尿的狼疮性肾炎多使用免疫抑制剂治疗，缺少靶向治疗药物。cGAS-STING是双链DNA诱发自身免疫反应的重要信号通路，在狼疮性肾炎中的调控机制不明。申请者在前期研究发现STING在狼疮性肾炎小鼠模型肾小球中表达增加，且与足细胞粘附及足突形成相关。组蛋白去乙酰化酶HDAC3抑制剂可以维持足细胞的骨架形态。故提出如下科学假说：在狼疮性肾炎中cGAS-STING信号通路激活，影响足细胞细胞连接功能造成蛋白尿的产生。HDAC3抑制剂通过抑制cGAS去乙酰化，靶向抑制cGAS-STING信号通路治疗狼疮性肾炎。本课题拟通过细胞、动物实验阐述组蛋白去乙酰化酶HDAC3调控cGAS-STING信号通路在狼疮性肾炎足细胞损伤中的机制，为HDAC3抑制剂治疗狼疮性肾炎提供理论依据。

Lupus nephritis is the most common secondary immune glomerular disease in China. It is one of the common causes of end-stage renal disease. At present, immunosuppressant therapy is used for lupus nephritis with clinical manifestations of large amounts of proteinuria, and there is a lack of targeted therapy drugs. cGAS-STING is an important signaling pathway of autoimmunity induced by double-stranded DNA, but the mechanism of its regulation in lupus nephritis is still unclear. In the previous study, we found that the expression of STING was increased in the glomerulus of mouse model of lupus nephritis and was related to podocyte adhesion and podocyte process formation. Histone deacetylase HDAC3 inhibitor can maintain podocyte's skeleton. Therefore, we put forward the following scientific hypothesis: In lupus nephritis, the activation of cGAS-STING signaling pathway affects the cell junction of podocytes, resulting in the production of proteinuria. HDAC3 inhibitor can inhibit cGAS deacetylation, thus is expected to treat lupus nephritis by blocking cGAS-STING signaling pathway. In this project, we intend to elucidate the mechanism of HDAC3 regulating cGAS-STING signaling pathway in podocyte injury in lupus nephritis by performing cell and animal experiments. This project will provide theoretical basis for the application of HDAC3 inhibitor against lupus nephritis.