Objective: This study aimed to investigate the role of PDK4 in vascular remodeling and gene expression changes related to extracellular matrix (ECM) dynamics in varicose veins, using both patient tissue data and experimental models. Methods: Transcriptomic and methylome analyses were performed on normal and varicose vein tissues to identify candidate genes. Varicose vein models were established in C57BL/6 and Pdk4 knockout mice by ligating the femoral vein. Morphological and histological changes were assessed two weeks post-surgery. Primary human umbilical vein smooth muscle cells (HUVSMCs) were cultured and transfected with shRNA targeting PDK4 to analyze changes in ECM-related gene expression. Quantitative real-time PCR and immunofluorescence staining were used to evaluate gene and protein expression.