Restenosis is the primary complication following stenting for coronary and peripheral arterial disease (PAD), posing an ongoing clinical challenge. Metabolic syndrome (MetS), characterized by metabolic disturbances, has been identified as an independent predictor for postoperative restenosis in coronary and carotid arteries, potentially due to endothelial dysfunction and augmented oxidative stress in cells, while its specific regulatory mechanism is still largely unknown. Lysine 2-hydroxyisobutyrylation (Khib), a recently identified post-translational modification, plays a crucial role in transcriptional regulation and cellular metabolism. However, there is a lack of comprehensive analysis of the proteome and Khib modifications within restenotic vessels in the context of MetS, as well as in the understanding of the associated pathophysiology. Here, we firstly validate changes in expression and distribution of Khib in vascular tissues in clinical tissue and cell models. Subsequently, we utilized proteomics and modifiomics to examine the protein and Khib modification characteristics in MetS-induced restenosis.