DBC1通过调控Nrf2乙酰化修饰介导类风湿关节炎成纤维样滑膜细胞铁死亡抵抗的机制研究

成纤维样滑膜细胞（FLS）是类风湿关节炎（RA）中侵袭破坏软骨和骨的主要效应细胞。申请者前期已有研究报道，FLS过度增殖和凋亡抵抗在RA发病中至关重要。然而，其他程序性死亡在RA-FLS中的作用尚不明确。我们在近期实验中发现，RA-FLS存在铁死亡抵抗，且与抗氧化因子Nrf2的活化以及细胞周期凋亡相关基因DBC1的过表达有关。进一步实验表明，敲低DBC1可抑制Nrf2的核内定位和蛋白表达、下调下游铁死亡相关基因的转录，但不影响Nrf2的mRNA水平。DBC1是去乙酰化酶SIRT1的重要调控因子。据此我们推测，DBC1过表达可能通过调控Nrf2乙酰化修饰介导RA-FLS铁死亡抵抗。本项目拟通过临床标本、细胞模型、DBC1基因敲除小鼠和胶原诱导型关节炎小鼠，结合体内外功能实验、蛋白互作实验，进一步阐明RA-FLS铁死亡抵抗的具体机制，为RA治疗提供新靶点、新思路。

Fibroblast-like synoviocytes (FLS) are the main effector cells that invade and destroy cartilage and bone in rheumatoid arthritis (RA). The applicant has reported that hyperproliferation and anti-apoptosis of FLS play crucial rules in the pathogenesis of RA. However, the functions of other programmed cell death in RA-FLS are not clear. In previous experiments, We found that RA-FLS has ferroptosis resistance, which is related to the activation of antioxidant factor Nrf2 and the overexpression of the cell cycle apoptosis regulating gene DBC1. Further experiments showed that knocking down DBC1 can inhibit the intranuclear localization and expression of Nrf2, and suppress the transcription of downstream ferroptosis-related genes, but do not affect the Nrf2 mRNA level. DBC1 negatively regulates the deacetylase SIRT1. Based on this, we speculate that DBC1 overexpression may mediate RA-FLS ferroptosis resistance by regulating acetylation of Nrf2. This project intends to further clarify the specific mechanism of RA-FLS anti-ferroptosis through clinical specimens, cell models, DBC1 knockout mice and collagen-induced arthritis mice, combined with in vivo and in vitro functional experiments, and protein interaction experiments, providing new targets and new ideas for future treatment.