Depression is a major threat to global mental health and demands targeted therapeutic regimens. The current study set out to evaluate the regulatory mechanism of nuclear factor erythroid-2 related factor 2 (Nrf2) in depression-induced cognitive dysfunction and inflammatory injury. First, depressive rat models were established via chronic unpredicted mild stress (CUMS) treatment. Cognitive function of rats was assessed by a series of behavioral tests. Rats were further stereotactically injected with Nrf2 overexpression vector, with expression patterns of Nrf2, miR-17-5p, and wolfram syndrome 1 (Wfs1) detected using qRT-PCR and Western blot assay. In addition, pathological changes of murine hippocampus were analyzed using hematoxylin–eosin staining. In vitro cell models were additionally established using lipopolysaccharide. Cell viability was detected via the CCK-8 method. Moreover, levels of TNF-α, IL-1β, and IL-10 were detected via ELISA. Furthermore, the binding relationships between Nrf2 and the miR-17-5p promoter, miR-17-5p, and Wfs1 were verified. It was found that Nrf2 was weakly expressed in CUMS-treated rats, whereas Nrf2 upregulation alleviated cognitive dysfunction and brain inflammatory injury. Meanwhile, Nrf2 inhibited miR-17-5p expression via binding to the miR-17-5p promoter. miR-17-5p was also found to limit Wfs1 transcription. miR-17-5p overexpression or Wfs1 downregulation partly reversed the role of Nrf2 in reliving inflammatory injury of murine hippocampal neurons. Overall, our findings indicated that Nrf2 inhibited miR-17-5p expression and promoted Wfs1 transcription, thereby alleviating cognitive dysfunction and inflammatory injury in rats with depression-like behaviors.

抑郁症是对全球心理健康的主要威胁，需要有针对性的治疗方案。目前的研究旨在评估核因子 erythroid-2 相关因子 2 (Nrf2) 在抑郁症引起的认知功能障碍和炎症损伤中的调节机制。首先，通过慢性不可预测的轻度压力（CUMS）治疗建立抑郁大鼠模型。通过一系列行为测试评估大鼠的认知功能。大鼠进一步立体定向注射 Nrf2 过表达载体，使用 qRT-PCR 和蛋白质印迹法检测 Nrf2、miR-17-5p 和 wolfram 综合征 1 (Wfs1) 的表达模式。此外，使用苏木精-伊红染色分析小鼠海马的病理变化。另外使用脂多糖建立了体外细胞模型。通过CCK-8方法检测细胞活力。此外，通过ELISA检测TNF-α、IL-1β和IL-10的水平。此外，验证了 Nrf2 与 miR-17-5p 启动子、miR-17-5p 和 Wfs1 之间的结合关系。发现 Nrf2 在 CUMS 治疗的大鼠中表达较弱，而 Nrf2 上调可减轻认知功能障碍和脑炎性损伤。同时，Nrf2 通过与 miR-17-5p 启动子结合来抑制 miR-17-5p 的表达。还发现 miR-17-5p 可以限制 Wfs1 转录。miR-17-5p 过表达或 Wfs1 下调部分逆转了 Nrf2 在缓解小鼠海马神经元炎症损伤中的作用。总体而言，我们的研究结果表明 Nrf2 抑制 miR-17-5p 表达并促进 Wfs1 转录，