LINC01419–miR-132-3p–USP38 axis mediates high glucose-induced ferroptosis in vascular endothelial cells

Abstract

Abstract Long non-coding RNA LINC01419 has been implicated in ferroptosis in various pathological conditions, yet its role in type 2 diabetes mellitus (T2DM) associated vascular endothelial dysfunction remains unclear. This study investigated the mechanism by which LINC01419 modulates ferroptosis in human vascular endothelial cells under high-glucose conditions. A high-glucose cellular model was established to evaluate cell proliferation, ferroptosis, and oxidative stress. Bioinformatics predictions and dual-luciferase reporter assays confirmed direct interactions between LINC01419 and miR-132-3p, and between miR-132-3p and ubiquitin-specific peptidase 38 (USP38). Quantitative real-time PCR validated regulatory interactions within the LINC01419/miR-132-3p/USP38 axis. Cell viability, reactive oxygen species levels, and ferroptosis markers were assessed via CCK-8, ROS detection, and Western blotting. Results showed that high glucose upregulated LINC01419 and USP38, downregulated miR-132-3p, elevated ROS, suppressed proliferation, and induced ferroptosis, as evidenced by increased ACSL4 and COX2 and decreased FTH1 and GPX4. LINC01419 acted as a competing endogenous RNA for miR-132-3p, and both molecules oppositely regulated USP38 expression. Notably, USP38 knockdown reversed high-glucose-induced abnormalities, restoring proliferation and ferroptosis-related protein expression. These findings reveal that the LINC01419/miR-132-3p/USP38 axis mediates ferroptosis in vascular endothelial cells under hyperglycemia, and suggest USP38 as a potential therapeutic target for T2DM.