Enhanced 5-methylcytosine methylation of PSD4 facilitates vasculogenic mimicry in breast cancer brain metastases through ferroptotic resistance.

During the metastatic progression of cancer, tumor cells undergo widespread genetic and epigenetic alterations. The regulatory mechanism of 5-methylcytosine (mC) methylation of PSD4 in breast cancer brain metastasis (BCBM) remains unclear. In this study, we found that PSD4 expression is markedly elevated in both BCBM tissues and cell lines. Functional assays in vitro revealed that overexpression of PSD4 significantly promoted cell proliferation, invasion, migration, and epithelial-to-mesenchymal transition (EMT). Complementary in vivo experiments confirmed the tumor-promoting and metastasis-enhancing roles of PSD4 in brain metastases. At the mechanistic level, PSD4 mC methylation was regulated by NSUN2 via its catalytic domains (C271A/C321A), which enhanced PSD4 mRNA stability and facilitated its nuclear export, increasing its expression. Furthermore, YBX1 was identified as a critical mC-binding protein regulating PSD4 methylation. Functional analysis also showed that PSD4 contributes to vasculogenic mimicry (VM) by promoting ferroptosis resistance, decreasing vascular permeability, and enhancing tumor growth and metastasis to the brain. These findings establish PSD4 as a key player in BCBM and suggest its potential as a diagnostic marker and therapeutic target.