Diabetic retinopathy (DR) is a serious microvascular complication of diabetes. The aim of this study was to explore the effect of Sestrin2 on DR through the regulation of autophagy and ferroptosis levels and its mechanism. In vitro and in vivo DR models were established by high glucose (HG) and streptozotocin (STZ) induction of ARPE-19 human retinal pigment epithelial cells and C57BL/6 mice, respectively. In this study, we demonstrated that after HG treatment, the activity of ARPE-19 cells was decreased, the apoptosis rate was increased, endoplasmic reticulum (ER) stress was activated, autophagy levels were decreased, and ferroptosis levels were increased. Overexpression of Sestrin2 enhanced cell viability, reduced apoptosis and ferroptosis, and enhanced autophagy. However, the effect of overexpression of Sestrin2 was attenuated after the addition of the STAT3 phosphorylation activator Colivelin TFA (C-TFA), the mTOR pathway activator MHY1485 or the autophagy inhibitor 3-methyladenine (3-MA). In addition, the effect of Sestrin2 knockdown on cells was opposite to the effect of overexpression of Sestrin2, while the effect of Sestrin2 knockdown was attenuated after treatment with the ER stress inhibitor 4-phenylbutyric acid (4-PBA). Animal experiments also confirmed the results of cell experiments and attenuated the effects of overexpression of Sestrin2 after injection of the ferroptosis activators erastin or 3-MA. Our study revealed that Sestrin2 inhibits ferroptosis by inhibiting STAT3 phosphorylation and ER stress and promoting autophagy levels, thereby alleviating DR.

糖尿病视网膜病变（DR）是糖尿病的一种严重的微血管并发症。本研究旨在探讨Sestrin2通过调节自噬和铁死亡水平对DR的影响及其机制。分别通过高糖（HG）和链脲佐菌素（STZ）诱导ARPE-19人视网膜色素上皮细胞和C57BL/6小鼠建立体外和体内DR模型。在本研究中，我们证明HG处理后，ARPE-19细胞活性降低，凋亡率增加，内质网（ER）应激被激活，自噬水平降低，铁死亡水平增加。Sestrin2 的过度表达增强了细胞活力，减少了细胞凋亡和铁死亡，并增强了自噬。然而，在添加 STAT3 磷酸化激活剂 Colivelin TFA (C-TFA)、mTOR 通路激活剂 MHY1485 或自噬抑制剂 3-甲基腺嘌呤 (3-MA) 后，Sestrin2 过表达的效果减弱。此外，Sestrin2敲低对细胞的影响与Sestrin2过表达的影响相反，而Sestrin2敲低的作用在用ER应激抑制剂4-苯基丁酸（4-PBA）处理后减弱。动物实验也证实了细胞实验的结果，并减弱了注射铁死亡激活剂erastin或3-MA后Sestrin2过度表达的影响。我们的研究表明，Sestrin2 通过抑制 STAT3 磷酸化和 ER 应激并促进自噬水平来抑制铁死亡，从而减轻 DR。