Epitranscriptomic Control of Vascular Smooth Muscle Cell Ferroptosis by WTAP in the Pathogenesis of Vascular Restenosis

AIMS: Vascular restenosis is a common complication following vascular interventions, driven by abnormal proliferation and phenotypic switching of vascular smooth muscle cells (VSMCs). Ferroptosis, an iron-dependent regulated cell death, has been implicated in VSMC dysfunction and vascular remodeling. However, the epitranscriptomic regulation of ferroptosis in VSMCs remains unclear.This study investigates the role of Wilms tumor suppressor gene WT1-associated protein (WTAP), a key N6-methyladenosine (m6A) RNA methylation regulator, in controlling ferroptosis of VSMCs during vascular restenosis. RESULTS: YTH domain family member 1. GAS5 inhibited EZH2-mediated H3K27me3 repression of IRF4, which transcriptionally activated FTH1, suppressing ferroptosis. WTAP overexpression decreased ROS, lipid peroxidation, and VSMC proliferation, while knockdown of GAS5 or IRF4 partially reversed these effects. INNOVATION: Our study is the first to identify that the WTAP/GAS5/IRF4 axis suppresses PDGF-BB-induced cell proliferation by inhibiting ferroptosis in VSMCs, and alleviates vascular restenosis caused by balloon injury. CONCLUSION: 44, 726-747.