胎盘发育不足会引发各种产科并发症，包括胎儿生长受限（FGR）。已经证实，Sirtuin 1（SIRT1）和胰岛素样4（INSL4）蛋白编码基因在胎盘发育中起重要作用。然而，由于胎盘功能障碍，目前没有可治疗FGR的方法。因此，本研究旨在研究SIRT1-INSL4轴作为治疗胎盘发育不足引起的FGR的候选治疗方法的潜力。本研究纳入了20名患者，其中包括10名FGR患者和10名足月控制组。收集了FGR和控制组的胎盘样本。采用定量实时聚合酶链反应、免疫组织化学分析和免疫印迹分析来分析INSL4和SIRT1的表达。采用人绒毛膜细胞癌细胞株BeWo进行体外功能分析，通过沉默SIRT1来将BeWo细胞分化为绒毛膜细胞。在将SIRT1沉默的BeWo细胞分化为绒毛膜细胞过程中加入SIRT1激活剂。FGR样本中INSL4和SIRT1的mRNA和蛋白表达水平低于对照组样本。免疫组织化学显示，SIRT1和INSL4主要在绒毛膜细胞中表达。体外分析表明，SIRT1沉默会降低INSL4的表达，但SIRT1激活剂可以恢复SIRT1沉默的BeWo细胞中的SIRT1表达。研究结果表明，FGR胎盘中SIRT1和INSL4的表达下调，而INSL4受SIRT1调控。这些发现表明SIRT1-INSL4轴可能是治疗FGR的潜在治疗靶点。

Insufficient placental development causes various obstetric complications, including fetal growth restriction (FGR). The Sirtuin 1 (SIRT1) and insulin-like 4 (INSL4) protein-coding genes have been demonstrated to play an important role in placental development. However, no treatment for FGR is available due to placental dysfunction. Therefore, this study aimed to examine the potential of the SIRT1-INSL4 axis as a treatment candidate for FGR caused by insufficient placental development.Twenty patients were enrolled, including 10 with FGR and 10 full-term controls. FGR and control placental samples were collected. Quantitative real-time polymerase chain reaction, immunohistochemical analysis, and western blotting were used to analyze INSL4 and SIRT1 expression. An in-vitro loss-of-function approach with the human choriocarcinoma cell line BeWo was applied for functional analyses of SIRT1 in placental development. BeWo cells were differentiated into syncytiotrophoblasts by silencing SIRT1 using small interfering RNA. SIRT1 activator was added during differentiation of SIRT1-knockdown BeWo cells into syncytiotrophoblasts.The FGR samples had lower INSL4 and SIRT1 mRNA and protein expression levels than the control samples. Immunohistochemistry showed that both SIRT1 and INSL4 were expressed mainly in syncytiotrophoblasts. In-vitro analyses showed that SIRT1 knockdown decreased INSL4 expression; however, SIRT1 activator restored SIRT1 expression in SIRT1-silenced BeWo cells.SIRT1 and INSL4 are downregulated in the placenta of FGR, and INSL4 is regulated by SIRT1. These findings indicate that the SIRT1-INSL4 axis may be a potential therapeutic target for FGR.