Diabetes mellitus is a common chronic disease (Ogurtsova, da Rocha Fernandes, Huang et al., 2017). Diabetes mellitus type 2 typically leads to complications, such as long-term damage to vital organs, including eyes, kidneys, nerves, and cardiovascular system (Hinchliffe, Brownrigg, Andros et al., 2016,Yang, Shi, Li et al., 2019,Zhou, Chai, Yang et al., 2023). The most prevalent ocular complication in diabetic patients is diabetic retinopathy (DR). In recent years, the number of DR patients has increased proportionally to the number of diabetic patients, garnering substantial attention (Ji, Han, Wang et al., 2020). Long-term cumulative damage to the retinal microvasculature from hyperglycemia is a key factor in DR (Duh, Sun and Stitt, 2017), which is also a major cause of blindness and other retina-related diseases (e.g., diabetic macular edema) (Duh et al., 2017).

Early stages of DR are characterized by retinal microangiopathy with pericyte loss and loss of retinal microvascular endothelial cells (RMECs), leading to increased microvascular permeability, retinal ischemia, and hypoxia, and ultimately to pathologic angiogenesis in proliferative DR (Hammes, 2018). According to previous studies, microvascular endothelial cell damage and retinal microvascular dysfunction are caused by multiple pathogenic variables, including decreased cell proliferation, apoptosis, and enhanced oxidative stress in a high-glucose environment (Ji et al., 2020,Wang, Yu, Wang et al., 2022,Zhan, Zhao, Shi et al., 2023). It suggests that malfunctioning of retinal microvascular endothelial cells may account for a significant cause of retinal microangiopathy. Due to the complexity and pathogenesis of the condition, there is currently no viable treatment for early RMEC cell damage in DR. Therefore, it is crucial to investigate the mechanism of hyperglycemia-induced RMEC cell damage to manage and treat early DR.

Circular RNAs (CircRNAs) are a novel class of endogenous noncoding RNAs characterized by closed-loop structures and are widely expressed in the eukaryotic transcriptome (Lasda and Parker, 2014,Huang, Yang, Chen et al., 2017). Multiple studies have shown that CircRNAs, as competitive endogenous RNAs, target miRNAs by sponging, thereby influencing mRNA expression (Meng, Li, Zhang et al., 2017,Bai, Zhang, Han et al., 2018). Reportedly, CircRNAs were aberrantly expressed within multiple human diseases, such as cancer, neurodegeneration, cardiovascular diseases, and DR (Shao and Chen, 2016,Chen, Li, Tan et al., 2016). For example, CircSLC16A12 was able to promote high glucose-induced dysfunction of RMECs by regulating miR-140-3p/FGF2 (Wang et al., 2022), and CircZNF532 ameliorated diabetes-induced pericyte degeneration and retinal vascular dysfunction via inhibiting miR-29a-3p (Jiang, Liu, Li et al., 2020). Recent studies indicate that CircZNF609 can increase apoptosis, inflammatory response, and oxidative stress in human retinal epithelial cells induced by high glucose levels (Zeng, Luo, Fang et al., 2022). Moreover, silencing CircZNF609 was also previously reported to protect endothelial cell function and inhibit pathological angiogenesis in vivo (Liu, Yao, Li et al., 2017). However, the function of CircZNF609 in high glucose-induced RMECs remains unelucidated.

Herein, the effect of CircZNF609 on hRMECs damage in DR was explored. CircZNF609 was shown to be highly expressed within peripheral blood from DR patients and high glucose-induced hRMECs, and inhibition of CircZNF609 ameliorated high glucose-induced hRMECs injury. Furthermore, CircZNF609 was found to regulate high glucose-caused hRMECs injury by modulating miR-150-5p expression and miR-150-5p targeted gene expressions.