胰岛素抵抗IR是多囊卵巢综合征PCOS发病的重要病理特征，发生率可高达85%，严重影响患者的生育、生活质量和子代健康，但机制未明。本课题组外显子测序发现PCOS伴IR患者LNK基因突变率高，研究发现LNK可影响脂肪炎症导致糖耐量异常，但其是否通过脂肪代谢参与IR发生值得研究。预实验发现：PCOS伴IR患者的脂肪组织中，LNK表达显著升高；PCOS IR模型小鼠敲除LNK可降低其血清TG、FFA、hsCRP水平并减少脂肪肝发生，对IR有缓解作用；机制研究表明敲除LNK可上调葡萄糖转运蛋白Glut4，且LNK与胰岛素受体底物IRS1可形成蛋白复合物。因此提出科学假设：脂肪组织中LNK通过结合IRS-1调控胰岛素信号通路，下调Glut4，参与PCOS IR发生。本项目拟结合临床标本、动物模型和细胞实验阐明LNK调控葡萄糖转运参与IR发生的机制，为LNK作为PCOS IR潜在治疗靶点提供科学依据。

Insulin resistance (IR) is an important pathological feature of polycystic ovary syndrome (PCOS), with an incidence rate of up to 85%, which seriously affects the patient's fertility, quality of life, and offspring health, but the mechanism is unknown. The adaptor protein LNK is closely related to metabolic diseases. Our exome sequencing has found that the mutation rate of LNK gene in patients with PCOS and IR is high. Studies have found that LNK can affect adipose inflammation and impair glucose tolerance. Whether LNK is related to fat metabolism is worth further study. Our previous research found that: LNK expression was significantly increased in adipose tissue of patients with PCOS and IR. Knockout of LNK in PCOS IR model mice can reduce serum triglycerides, free fatty acids, high-sensitivity C-reactive protein levels and reduce fatty liver occurrence, which indicates that LNK has a mitigating effect on IR. Mechanism studies have shown that LNK knockout can upregulate the glucose transporter Glut4, also LNK and insulin receptor substrate IRS-1 can form protein complexes. Based on the above research basis, we propose the following scientific hypothesis: LNK in adipose tissue can regulate insulin signaling pathway by binding to IRS-1, downregulate Glut4, and participate in PCOS IR occurrence. This project intends to clarify the specific mechanism by which LNK regulates glucose transport and participate in IR in combination with clinical specimens, animal models and cell experiments, and provide scientific basis for LNK as a potential therapeutic target for PCOS IR.