Diabetic retinopathy (DR) is a diabetes-associated complication that poses a threat to vision, distinguished by persistent and mild inflammation of the retinal microvasculature. The activation of microglia plays a crucial role in driving this pathological progression. Previous investigations have demonstrated that ubiquitin-specific peptidase 25 (USP25), a deubiquitinating enzyme, is involved in the regulation of immune cell activity. Nevertheless, the precise mechanisms through which USP25 contributes to the development of DR remain incompletely elucidated. Firstly, we have demonstrated the potential mechanism by which ROCKs can facilitate microglial activation and augment the synthesis of inflammatory mediators through the modulation of NF-κB signaling pathways in a high-glucose milieu. Furthermore, our study has provided novel insights by demonstrating that the regulatory role of USP25 in the secretion of proinflammatory factors is mediated through the involvement of ROCK in modulating the expression of NF-κB and facilitating the nuclear translocation of the phosphatase NF-κB. This regulatory mechanism plays a crucial role in modulating the activation of microglial cells within a high-glycemic environment. Hence, USP25 emerges as a pivotal determinant for the inflammatory activation of microglial cells, and its inhibition exhibits a dual effect of promoting retinal neuron survival while suppressing the inflammatory response in the retina. In conclusion, the promotion of diabetic retinopathy (DR) progression by USP25 is attributed to its facilitation of microglial activation induced by high glucose levels, a process mediated by the ROCK pathway. These findings highlight the importance of considering USP25 as a potential therapeutic target for the management of diabetic neuroinflammation.

糖尿病视网膜病变 (DR) 是一种糖尿病相关并发症，对视力构成威胁，其特点是视网膜微血管系统持续轻度炎症。小胶质细胞的激活在驱动这种病理进展中起着至关重要的作用。先前的研究表明，泛素特异性肽酶 25 (USP25)，一种去泛素化酶，参与免疫细胞活性的调节。然而，USP25 促进 DR 发展的确切机制仍未完全阐明。首先，我们证明了 ROCK 在高血糖环境中通过调节 NF-κB 信号通路促进小胶质细胞激活并增强炎症介质合成的潜在机制。此外，我们的研究提供了新的见解，证明 USP25 在促炎因子分泌中的调节作用是通过 ROCK 参与调节 NF-κB 的表达和促进磷酸酶 NF-κB 的核转位来介导的。这种调节机制在调节高血糖环境中小胶质细胞的激活方面发挥着至关重要的作用。因此，USP25成为小胶质细胞炎症激活的关键决定因素，其抑制表现出促进视网膜神经元存活和抑制视网膜炎症反应的双重作用。总之，USP25 促进糖尿病视网膜病变 (DR) 进展归因于它促进高葡萄糖水平诱导的小胶质细胞激活，这是一个由 ROCK 通路介导的过程。这些发现强调了将 USP25 视为治疗糖尿病神经炎症的潜在治疗靶点的重要性。