WW Domain‐Binding Protein 2 Aggravates Neointimal Hyperplasia by Promoting Y‐Box Binding Protein 1 Nuclear Translocation

ABSTRACT Cardiovascular interventional therapy continues to face a major challenge in clinical practice due to the presence of restenosis after PCI. Continuous exploration uncovers novel signaling molecules implicated in this pathophysiological process. However, the precise molecular mechanism remains elusive. The WW domain‐binding protein 2 (WBP2) has emerged as a notable oncoprotein, serving as a central hub that links multiple signaling pathways in cancer, including EGFR, PI3K, Hippo, and Wnt. Nevertheless, its role in vascular biology remains ambiguous. This study aims to elucidate the role of WBP2 in neointimal hyperplasia (NIH) as well as vascular smooth muscle cell (VSMC) proliferation after vascular injury. The mice carotid artery ligation (CAL) model revealed increased WBP2 expression after vascular injury, which was further confirmed by PDGF‐BB stimulation in VSMCs. Histopathological analysis was performed to assess the extent of NIH in the CAL mouse model. Additionally, FUCCI and Transwell assays were used to evaluate VSMC proliferation and migration, respectively. WBP2 knockdown alleviated neointimal thickening and VSMC proliferation following vascular injury, in stark contrast to the significant increase observed with WBP2 overexpression. Mechanistically, we demonstrated that WBP2 interacts with Y‐box binding protein 1 (YBX1) and enhances the binding of RSK to YBX1, promoting YBX1 S102 phosphorylation, which facilitates its nuclear translocation. This subsequently activates proliferative genes and represses contractile genes, thereby contributing to the development of NIH. Our findings suggest that WBP2 may promote NIH and VSMC proliferation by facilitating the nuclear translocation of YBX1. Therefore, WBP2 could serve as a promising target for the management of restenosis.