INTRODUCTION: The proprotein convertase subtilisin/kexin type 9/lectin-like oxidized low-density lipoprotein receptor-1 (PCSK9/LOX-1) axis plays a crucial role in regulating vascular endothelial cell function, but its specific involvement in type 2 diabetes mellitus (T2DM) remains unclear. This study aims to explore the potential mechanism of the PCSK9/LOX-1 axis in high-glucose (HG)-induced vascular endothelial cell dysfunction. MATERIAL AND METHODS: Peripheral blood samples were collected from T2DM patients to analyse the correlation between PCSK9 and blood lipid levels. Human microvascular endothelial cells (HMEC-1) exposed to high glucose concentration were used as a model of diabetic=angiopathy (DA). Levels of PCSK9, reactive oxygen species (ROS), malonodialdehyde (MDA), interleukins (IL): IL-6, IL-1β, superoxide dismutase (SOD), and tumour necrosis factor alpha (TNF-α) were determined by enzyme-linked immunosorbent assay (ELISA) and biochemical methods. Additionally, intracellular total cholesterol (TC) and cholesterol ester (CE) levels were detected using enzyme chemistry. Expression of PCSK9 and LOX-1 was assessed through real-time quantitative polymerase chain reaction (RT-qPCR) and western blotting. RESULTS: Compared to the normal group, PCSK9 levels were significantly elevated in T2DM patients. Furthermore, PCSK9 levels were found to be positively correlated with body mass index (BMI), waistline, triglyceride (TG), cholesterol, low-density lipoprotein cholesterol (LDL-C), glycated hemoglobin (HbAlc), and intracardiac fat pad levels in T2DM patients. HG exposure led to reduced activity of HMEC-1 cells, along with increased levels of apoptosis, oxidative stress, and inflammation, all of which were counteracted by si-PCSK9. The inhibitory effects of si-PCSK9 on LOX-1 expression, as well as TC and CE contents in HMEC-1 cells induced by HG, were observed. Moreover, intervention with oe-LOX-1 reversed the effects of si-PCSK9 in HG-induced HMEC-1 cells. CONCLUSION: Silencing of PCSK9 inhibited HG-induced inflammation, oxidative stress, and lipid metabolic dysfunction in HMEC-1 cells via LOX-1.