Neointimal Hyperplasia and Restenosis: Epidemiology, Pathophysiology, Animal Models, Clinical Features, Diagnosis, and Management.

In-stent restenosis (ISR) remains a major complication following vascular interventions, with neointimal hyperplasia representing a central pathological process that can adversely affect postoperative outcomes. Accumulating evidence indicates that neointimal hyperplasia is driven by vascular smooth muscle cell (VSMC) phenotypic transition, endothelial dysfunction, inflammation, and multiple forms of programmed cell death. Despite substantial advances, the underlying pathogenic mechanisms remain incompletely understood. This review comprehensively examines neointimal hyperplasia from the perspectives of epidemiology, pathophysiology, preclinical animal models, clinical manifestations, diagnostic approaches, and therapeutic strategies. Particular attention is given to the emerging associations between recently characterized forms of programmed cell death, including ferroptosis and cuproptosis, and neointimal hyperplasia. In addition, commonly used preclinical animal models are reviewed, together with potential therapeutic approaches such as colchicine and vasostatin-2 and their underlying mechanisms. The diagnostic roles of invasive imaging and noninvasive modalities in evaluating neointimal hyperplasia are discussed, with emphasis on their respective advantages and limitations. Furthermore, current stent-based strategies, pharmacological therapies, and alternative interventions for ISR are summarized, along with critical consideration of their limitations and potential avenues for improvement. By integrating mechanistic evidence with available therapeutic options, this review aims to provide a comprehensive theoretical framework for the clinical management of ISR.