• High glucose upregulates ZIPK, STAT5A, p53, and NOS2 in HUVECs, leading to increased oxidative stress.
• ZIPK interacts with STAT5A in the nucleus under high-glucose conditions, and silencing ZIPK or STAT5A reduces ROS accumulation and p53/NOS2 expression.
• The ZIPK inhibitor TC-DAPK6 decreases ZIPK, p53, and NOS2 expression in diabetic rats, suggesting therapeutic potential.
• ZIPK is a promising target for mitigating diabetic vascular complications via the STAT5A/p53/ROS pathway.